Interaction of phospholipids with proteins and peptides. New advances III

ht. .I. Eiochem. Vol. 25, No. 2. pp. 123-146,1993

0020-7 I I X/93 $24.00 + 0.00 Copyright C 1993 Pergamon Press Ltd

Printed in Great Britain. All rights reserved

REVIEW

INTERACTION OF PHOSPHOLIPIDS WITH PROTEINS AND PEPTIDES. NEW ADVANCES III T. CSERHKTI’ and M.

Szijc~t~

‘Central Research Institute for Chemistry, Hungarian Academy of Sciences, P.O. Box 17, H-1525 Budapest, Hungary and %stitute of Biophysics, Semmelweis Medical University, Budapest, Hungary (Received 25 June 1992) Abstract-l. The review deals with the recent achievements in the study of the various interactions of phospholipids with proteins and peptides. 2. The interactions are classified according to the hydrophobic, hydrophilic or mixed character of the interactive forces. 3. The effect of the interaction on the structure and biological activity of the interacting molecules is also discussed.

living organism studied. However, due to the complexity of the system the results cannot be generalized, and valid theoretical conclusions cannot be drawn from the data. The poor solubility of phospholipids in aqueous biological environment makes questionable the applicability of such experimental designs. Ultracentrifugation separates molecular complexes according to their molecular mass independently of their composition that can result in the misinterpretation of the data. In the majority of cases the results obtained by ultra-centrifugation need separate methods to verify the phospholipid-protein complex formation. Chromatographic methods are more suitable for the study of such interactions than the ultracentrifugation. However, complexes with weak connecting forces are liable to dissociation during the chromatographic process. In these instances one of the interacting agents has to be added to the eluent, the change of retention is the indicator of the complex formation. According to our knowledge this last method has never been applied to study phospholipid-protein interaction. Determination of the activity of various enzymes in the absence and in the presence of phospholipids contains valuable information about the involvement of phospholipids in the regulation of biological processes. This method is extensively and successfully applied, the results of various research groups show good correlation proving the validity of these types of experiments. However, the method does not contain information about the underlying biophysical or biochemical phenomena (structural change of the proteins, hydrophobic or hydrophilic character of the interaction, number and type of interacting molecular substructures etc.) that has to be elucidated by other methods.

INTRODUalON Last

decade

interaction

the number of membrane

of studies

dealing

phospholipids

with the

with proteins

and

peptides continuously increased. Many biological processes occur on the semipermeable membrane of the cells composed of phospholipids and various peptides and proteins. Numerous chemical, biochemical and biophysical methods have been used to elucidate the various aspects of the interaction between these molecular species. The advantage of the biological method is the direct assessment of the effect of phospholipids on the Abbreviations: CH, cholesterol; CL, cardiolipin; DDPC, didezanoylphosphatidylcholine; DHPC, dihexanoylphosphatidylcholine; DLinPC, dilinoleoylphosphatidylcholine; DLinPE, dilinoleoylphosphatidylethanolamine; DLPC, dilauroylphosphatidylcholine; DMPA, dimyristoylphosphatidic acid; DMPC, dimyristoylphosphatidylethenolamine; DMPG, dimyristoylphosphatidylglycerol; DMPS, dimyristoylphosphatidylserine; DOPC, dioleoylphosphatidylcholine; DOPE, dioleoylphosphatidylethanolamine; DOPS, dioleoylphosphatidylserine; DPhPC, diphytanoylphosphatidylcholine; DPPA, dipalmitoylphosphatidic acid; DPPC, dipalmitoylphosphatidylcholine; DPPE, dipalmitoylphosphatidylethanolamine; DPPS, dipalmitoylphosphatidylserine; DSPC, distearoylphosphatidylcholine; PA, phosphatidic acid; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PG. phosphatidylglycerol; PI, phosphatidylinositol; PIP,, phosphatidylinositol 45 bisphosphate; PLinPC, palmitoyllinoleoylphosphatidylcholine; POPC, palmitoyloleoylphosphatidylcholine; POPE, palmitoyloleoylphosphatidylethanolamine; POPS, palmitoyloleoylphosphatidylserine; PS, phosphatidylserine; PSPC, palmitoylstearoylphosphatidylcholine; SM, sphyngomyelin. 123

124

T. CSERH~TI and M.

The advantages and drawbacks of the application of enzyme-linked immunosor~nt assays to study protein-phospholipid interactions are similar to those of traditional enzymatic methods (data simply state the occurrence of interaction but do not define its character). As it uses considerably lower quantities of enzyme and phospholipids its application probably will rapidly increase. Fluorescence spectrometry and its numerous variations are extensively used for the study of phospholipid-protein interactions. The main advantage of the methods are the high sensitivity and the wide variety of fluorescence probes (hydrophobic or hydrophilic character) that makes the methods suitable for the study of a high number of interactions. However, the calculation of the strength of interaction is hardly possible from the data of fluorescence spectroscopy. The main advantages of the infrared methods is that the involvement of individual molecules in the interaction can be determined. This information may help the elucidation of the mode of interaction at the molecular level. However, in the instances of biomolecules of high molecular mass the sensitivity of the methods considerably deteriorates what makes its application questionable. Circular dichroism produces valuable information about the structural changes of peptides and proteins interacting with phospholipids but does not define directly the molecular substructures accounting for the interaction. In combination with other biophysical methods it is frequently used mainly for the elucidation of peptide structures interacting with liposomes. The data concerning the successful application of X-ray and neutron diffraction methods are fairly rare. They are promising approximations for the determination of structural changes, however, their field of application has not been yet concretely defined, and the number of studies is low to draw genera1 conclusions. Electron microscopy can atso produce visual information about very complicated protein-phospholipid assemblies. However, the data obtained by electron microscopy have to be treated cautiously. It has never been proved that the images reflect real biological structures and are not the artifact of the sample preparation. The application of various NMR techniques markedly contributed to the elucidation of many aspects of protein-phospholipid interactions. They are powerful and versatile methods with some decrease in performance in the higher molecular mass region. Electron spin resonance together with fluorescence spectroscopy, CD and NMR are extensively used in the elucidation of the various aspects of protein.-phospholipid interactions. Special consideration has to be devoted to the fact that the data obtained by ESR can reflect the structural modification caused by the spin label and not the effect of the interaction to be studied. The application of differential scanning calorimetry is restricted to the molecules that show phase transition phenomenon. Oppositely to the most method applied for the study of protein-phospholipid interactions

Sziic;ui

differential scanning calorimetry gives direct information about the enthalpy of the interaction but does not define the molecular substructures accounting for the enthalpy change. Conductivity measurements can explore the channel forming capacity of peptides and proteins, and can determine the characteristics of channel. With the change of the environment valuable data can be obtained on the selectivity of channels. The determination of the permeability change of liposomes caused by peptide or proteins may help the prediction of the biological activity of these molecules because the biological activity of many peptides and proteins is based on their capacity to disorganize phospholipid membranes. This method proves the perturbation of the membrane structure but does not indicate the underlying reaction mechanism. The determination of the surface pressure of phospholipid monolayers in the absence and presence of peptides or proteins is also a good indicator of the interaction. However, the conclusions drawn from such type of measurements are limited and do not specify the character of the interaction. The objectives of the present review were to collect and to analyze the new experimental and theoretical data concerning the interaction of phospholipids with proteins and peptides and to classify them according to the hydrophobic or hydrophilic character of the interaction and according to the interacting molecular species. HYDROPHOBIC

INTERACTIONS

Peptides

Hydrophobic peptides inhibit the fusion of Sendai virus with N-methyl DOPE vesicles and human erythrocyte membranes (Kelsey et al., 1991). “P nuclear magnetic resonance spectroscopy was used to study phospholipid organization in hydrated preparations of N-methyl DOPE and a fusion peptide with the sequence: ~AG~~LAGAALG~AAAA~I, which corresponds to the amino terminus of the Fl subunit of the membrane fusion protein of measles virus. This hydrophobic peptide readily interacted with the large unilamellar vesicles (Yeagle et al., 1991). The hydrophobic peptide carbobenzoxy-Dinhibits the phenylalanyl-t_-phenylalanylglycine fusion of DPPC vesicles by inserting the phospholipid bilayer and stabilizing its structure (Yeagle et al., 1992). It was found that the coiling of analogs of Leu-Tyr-Gin-Glu-Leu-Gin-Lys-Leu-Tyr-Gin-ThrLeu-Lys on DPPC vesicles depends upon the strength and structure of its longitudinal hydrophobic strip (Lu et al., 1991). Time-resolved fluorescence energy transfer measurements led to the conclusion that melittin in fluid DMPC membranes is usually monomeric. Only at the high melittimlipid molar ratio of l/200 and high ionic strength evidence for aggregation was obtained. Supposedly, melittin monomers lie more or less flat on the membrane surface with the hydrophobic side of the melittin helix

Interaction of phospholipids with proteins and peptides making contact with the hydrophobic core of the lipid bilayer (John and Janig, 1991). In the presence of melittin at an egg PE-to-melittin molar ratio of 200, 100, and 20, the phase transition of PE disappeared, indicating that melittin stabilizes the bilayer structure. In the presence of CH, melittin displays hydrophobic interactions with PE (Nishiya and Chou, 1991). The channel-forming colicins encoded by the colicin plasmid of E. co& exert a lethal effect on sensitive E. coli by depolarizing and deenergizing the cells. The binding of a COOH-terminal channelforming thermolytic fragment of colicin El to asolectin vesicles has been studied by means of a variety of spectroscopic techniques. The structural changes observed indicate that the unfolding itself and/or successive hydrophobic interactions between membrane and the hydrophobic anchor of the channel might provide the peptide with free energy consumed in conversion from x-helical structure to p-sheet (Suga et al., 1991). A modification of Be18 to Asn in the peptide corresponding to an export-defective mutant OMpA signal sequence lowers the mean residue hydrophobicity and consequently reduces ability to bind and insert into membranes of POPE/ POPG 65/35 mol% (Hoyt and Gierasch, 1991b). The tryptophan-containing analogues of the wild-type signal peptide LamB insert into the acyl chain region of the 65%POPE/35% POPG lipid bilayer (M&night et al., 1991). Peptides corresponding to the wild-type signal sequence of the Escherichia coli outer membrane protein OmpA were synthesized and their ability to interact with 65/35 (mol%) mixture of POPEjPOPG was studied by circular dichroism carboxyfluoresceine leakage assay and steady-state fluorescence anisotropy measurements. It was established that the ability of the signal peptides to insert into membranes and their in aivo function correlate with the residue-average hydrophobicity of their hydrophobic cores (Hoyt and Gierasch, 1991af. The ol-aminoisobutiric acid containing antibiotic peptides, trichopolyn I and hypelcin A increase the permeability of PC vesicles. The peptides probably penetrate into the hydrophobic region of the bilayer (Matsuzaki et al., 1991~). The effect of 7 peptides based on the sequence of human pulmonary surfactant protein B on the molecular packing of DPPC! DPPG (7: 1) and DOPC was determined by fluorescence anisotropy. It was found that the hydrophobicity of peptides is a prerequisite for their effect (Baatz et al., 1991). The two hydrophilic peptides derived from apoIiprotein E were unable to bind to DMPC (Sparrow et al., 1992). Enzymes

Liver m~~rosomal cytochrome b, spontaneously associates with Iiposomes and membranes by means of its C-terminal hydrophobic domain. Dimeric proteins (P-galactoside + cytochrome b, C-terminal hydrophobic domain) prepared by genetic fusion also spontaneously associate with small unilamellar

125

vesicles of egg yolk PC. The spontaneous binding involves primarily hydrophobic, rather than ionic interactions (George et al., 1991). The nature of the polar group (i.e. choline, serine, ethenolamine or inositol) is not critical for the activity of P450 IIIAl isolated from rat liver microsomes. The results confirmed that P450 IIIAl activity is highly dependent on the fatty acid component of phospholipids (Eberhardt and Parkinson, 1991). The hydrophobicity of tailed A-symmetric acetylcholinesterase plays a considerable role in its attachment to rat superior cervical ganglion membranes (VerdiereSahuque et al., 1991). Other proteins

Negatively charged egg PC/dicetyl phosphate donor and neutral egg PC acceptor small unilamellar vesicles were used to study the transfer kinetics of human apoliproteins A-I, A-II and C-III. It was observed that the less hydrophobic molecules transfer more rapidly (Ibdah et al., 1991). Eukaryotic cells contain phosphoiipid transfer proteins that act as carriers of phospholipids between membranes. Phosphatidyl-transfer protein contains specific and independent hydrophobic binding sites for the sn-1 and sn-2 fatty acyl chains (Wirtz, 1991). In a Monte Carlo simulation study only hydrophobic interactions were supposed between a hypothetical protein and DPPC. According to the calculations the perturbations of the embedded protein extend up to a large number of lipid layers (Sperotto and Mouritsen, 1991a). According to an other simulation study the hydrophobic matching between the lipid and protein hydrophobic thicknesses were considered as a major contribution to the lipid-protein interactions. The model calculations predict that the lipid-mediated formation of protein aggregates in the membrane plane is mainly controlled by the strength of the direct lipid-protein hydrophobic attractive interaction (Sperotto and Mouritsen, 1991b). The effects of a homologous series of short-chain phospholipids from DHPC to DDPC on the nicotinic acetylcholineactivated ion channel in cultured rat muscle cells were investigated. All phospholipids markedly reduced the frequency of channel opening in a concentrationdependent manner. The more hydrophobic the molecule the more effective it was, and hence the higher its affinity to the binding site (Braun and 1991). The hydrophobic domain of Haydon, the phospholipids influences the channel forming capacity of ~rff~~~~ococ~~~ u~rtus z-toxin in PC : SM : CL membrane probably modulating the packing of phospholipids (Tomita et ai., 1992). It was emphasized in the excellent review on the cytolitic pore-forming proteins and peptides that these compounds form pores by simple lateral oligomerization of the monomers such that the hydrophobic side of the protein is exposed to the membrane acyl chains and the hydrophilic sides line up the pore (Ojcius and Young, 1991). The study of the binding of the

126

T.

CSERHATI and

brain-specific calmodulin-binding protein kinase C substrate, neuromodulin to PA, PG, PS and PI multilamellar vesicles proved the specific binding of neuromoduhn to negatively charged phospholipids through electrostatic interactions (Houbre et al., 1991). Mildly acidic pH induces the 63 kDa carboxyterminal fragment of protective antigen of anthrax toxin to become hydrophobic and enables it to release entrapped K + from asolectin liposomes (Koehler and Collier, 1991). The carbon number of the acyl chains of PE and PC determine to a large extent the activity of the branched-chain amino acid transport system of Lactococcus luctis (Veld et al., 1991). The O-toxin of Clostridium perjringens binds to large unilamellar liposomes composed of CL and PCjPG 82: 18 mol/ mol. Liposomes containing phospholipids with 18carbon hydrocarbon chains at both positions 1 and 2 of the glycerol have both high- and low-affinity binding sites, whereas liposomes with hydrocarbon chains containing 16 or fewer carbons at either position 1 or 2 have only low-affinity binding sites. The CL/phospholipid ratio, in addition to the length of phospholipid hydrocarbon chain, also determines the number of toxin-binding sites (Ohno-Iwashita et al., 1991). The uptake of liposome-encapsulated carboxyfluorescein by rat pulmonary alveolar macrophage was highest with unsaturated phospholipid preparations (Gonzalez-Rothi et al., 1991). SP-C, a highly hydrophobic, 3.7 kDa protein constituent of lung surfactant shows a trans-bilayer orientation in binary mixtures of DPPC and PPG (Pastrana et al., 1991). It has been assumed that the interaction between the hydrophobic amino acids and the lipid hydrocarbon backbone regulates the interaction of surfactant protein c with DPPC and PG (Vandenbussche er al., 1992). The incorporation of glycophorin into unilamellar CL-containing DMPC vesicles caused an enrichment of CL in the vicinity of the protein that indicates that CL interacts with hydrophobic interfaces of this erythrocyte protein (Tampe et al., 1991). CL showed affinity for the purified simian virus 40 large tumour antigen, PG with unsaturated fatty acids also showed binding affinity whereas PG with saturated fatty acids, PS, PI and PE do not (Hirai et al., 1991). The acyl chain unsaturation of phosphatidylcholine considerably influence the metarhodopsin I-metarhodopsin II equilibrium (Mitchell et al., 1992). HYDROPHILIC

INTERACTIONS

Peptides Mehttin induced voltage-dependent conductance in DOPC lipid bilayers. It was established that the charged groups of melittin are involved in the pore formation and conductance (Plawlak et al., 1991). [Ala-14]-melittin is less able to induce voltage-dependent ion conductance in planar POPC: DOPS: CL (75: 25: 5) planar bilayers than melittin. It was believed that the increased flexibility of [Ala-14]-melittin

M. Sziicv~

arises because proline is unique among the common amino acids in its inability to form a backbone hydrogen bond. [Ala-l4]-melittin has twice the hemolytic activity of melittin (Dempsey et al., 1991). The effective charge of melittin decreases considerably upon interaction with POPC vesicles (Beschiaschvili and Baeuerle, 1991). Amphiphilic tetrapeptide mastoparan (wasp venom toxin), bee venom melittin, cobra venom toxin cardiotoxin and polymyxin B inhibited protein kinase c stimulated by PS bilayer. Polypeptides showed discrete interactions with functionally distinct sites on the membrane, leading to differential inhibition of biological activities associated with the membrane. It is also possible that the lipid composition of the membrane could contribute to the difference (Raynor er al.. 1991). The antibiotic peptide AS-48 has been isolated from the culture supernatant of Enterococcus faecalis ssp liquefaciens S-48, it is rich in basic and neutral amino acids, its molecular mass is 7.4 kDa, and has an isoelectric point close to 10.5. Its antibacterial effect may be due to the capacity to form channels in PC planat bilayer membranes (Galvez et al., 1991). Toxin mastoparan X, the regulatory peptides ACTH( l-24) cz-MSH, ACTH(I-IO), dynirphin A, bombesin and LHRH display affinity for vesicles consisting of the acidic phosphohpid CL, the extent of which depends on the net positive charge of the peptide (De Kroon et al., 1991a). A pore-forming peptide of 4-5 kDa was isolated from the pathogenic Entamoeba histolytica. The peptide depolarized the membrane potential of (DOPC, PE, DOPG, PI, PS and SM) liposomes and was found to be optimally expressed at low pH. The N-terminal amino acid sequence of the amoeba peptide was structurally similar to melittin (Leippe et al., 1991). Magainins 1 and 2, isolated from Xenopus skin, are basic antimicrobial peptides with broad spectra. They promote the leakage of calcein from acidic lipid small unilamellar vesicles (DOPG, DPPG, bovine brain PS). An increase in salt concentration of the medium reduced binding and leakage. Electrostatic interactions play a crucial role in the binding process. The high concentration of salt may reduce electrostatic repulsions between the lipid head groups, tightening the membrane surface region (Matsuzaki et ul., 1991b). The measurements of surface pressure of monolayers at the air/water interface indicated that valinomycin interacts with the polar head group of the negatively charged mono-sialoglyco-sphingolipid and becomes partly embedded within the lipid interface (Schifferer ef al., 1991). A 27 amino acid peptide corresponding to a segment of the nicotinic acetylcholine receptor has 4 negatively and 3 positively charged residues on one side of the a-helix. It forms very stable ion channels in soybean asolectin bilayers (Ghosh and Stroud, 199 1). Four analogues of the membrane-modifying, a-helical polypeptide antibiotic alamethicin were synthesized and their interaction with the main tetraether lipid of the Archaebacterium Thermoplusmu

Interaction of phospholipids acidophilum, DPPC and dihexadecylmaltosylglycerol was studied with calorimetry. It was established that helix length, amphiphilicity and charge of the polypeptide can be correlated with the observed modifications of the lipid phase transitions (Blocher er al., 1991). The channel-forming capacity of synthetic basic peptides which mode1 the prepiece moiety of mitochondrial protein precursors and have antibacterial activity against Gram-positive bacteria was studied on asolectin and DPHPC bilayers. The effects of peptides on the macroscopic current-increase correlated with the antibacterial activity of these peptides (Anzai et al., 1991). Interferon-r binding to PC ‘PA liposomes was dependent on the liposomal charge and pH. NaCl considerably influences the interaction which indicates the involvement of ionic binding (Ishihara et al., 1991a). The annexins or lipocortins are a family of calcium-dependent phospholipid binding proteins. It was established that annexin V (placental anticoagulant protein I) binds tightly to anionic phosphohpid vesicles in the presence of calcium. His-204 and adjacent basic residues, including the highly conserved Arg-200 residue, are not required for high-affinity phospholipid binding (Tait and Smith, 1991). The fusion of hemagglutinin glycoprotein of influenza virus with phospholipid monolayers was detected by fluorescence video microscopy. The fusion rate increased as the pH was lowered. The monolayers were composed of lipid/ganghoside in molar ratios of 19: 1 or 9 : 1. The lipid consisted of 1: 1 asolectin/cholesterol and the ganglioside consisted of 1: 1 G,,,/G,,, (Niles and Cohen, 1991a). Other results showed that the pH dependence of influenza virion fusion arises from the interaction of the sialic acid receptor with the influenza hemagglutinin (Niles and Cohen, 1991 b). To assess the role of clusters of basic amino acids on many cytoplasmic proteins as well as on the cytoplasmic domain of many intrinsic membrane protein, the binding of peptides Lys, and Arg, to bilayer membranes containing PS or PC was determined. None of the peptides bound to vesicles formed from the zwitterionic PC but all bound to vesicles formed from PCjPS or PCjPG mixtures. None of the peptides exhibited specificity between PS and PG (Kim et al.. 1991). Peptides with amino acids equivalent to residues 19-36 and 19-29 of protein kinase c bound to negatively charged phosphohpid vesicles. The interaction of basic residues with acidic lipids in the membrane could provide 6 kcal/mol free energy towards stabilizing the active form of protein kinase c (Mosior and McLaughlin, 1991). Synthetic (ArgAla-Arg-Pro), polypeptides, the repeated regions of circumsporozoite proteins of Plasmodium fukiparum, interact with DMPC and DPPC membranes. The lipid-polypeptide interactions perturb both lipid polar and peptide backbone amide groups (Verdini et al., 1991). A recent review deals with the membrane insertion and lateral mobility of synthetic amphiphilic signal peptides in lipid model membranes. It empha-

with proteins and peptides

127

sizes the role of both hydrophobic and hydrophilic forces in the interaction, however, the relative impact of hydrophobic and hydrophilic forces in the interaction depend on the characteristics of the interacting peptide-phospholipid pair (Tamm, 1991). The interaction of the signal peptide of prePhoE with anionic phospholipid vesicles (DOPC and DOPS) resulted in the increase of cc-helix content. DOPC was ineffective to induce a-helix formation (Keller et al., 1992). The peptide antibiotic nisin differently interacts with liposomes composed from E. coli PE-egg PC (9 : 1 w/w), from egg PC and from asolectin as determined by fluorescence measurements (Gao et al., 1991). In a good review on the application of liposomes in the delivery of various drugs such as bioactive peptides etc., the importance of charge density, hydrophobicity and polarisability of the hposomal surface has been emphasized (Fielding., 1991). The K+ diffusion potential induced the association of synthetic model peptides with large unilamellar vesicles consisting of egg-PC and beef heart CL (De Kroon et al., 1991~). The binding of various synthetic peptides modeling human lung surfactant protein B to DPPCjPG multilayers was monitored by vibrational Raman spectroscopy. The peptides consisted of residues 59-8 1 of the human surfactant protein and 21 amino acid residue peptides containing repeated units of Arg separated by either 4 or 8 leucines. Peptides effectively stabilize the phospholipid bilayer assembly through electrostatic headgroup constraints; that is, the positively charged peptide moieties interact with the PG headgroups (Vincent et al., 1991). Synthetic amphiphilic anionic peptides can mimic the fusogenic activity of influenza hemagglutinin. They induce fusion of egg yolk PC small or large unilamellar vesicles only at acidic pH (Murata et al., 1991). Basic amphipathic a-helical peptides possess a highly potent ability to perturb the membrane structure of DPPC, PPG and DPhPC. The effect was higher with the increasing length of peptide chain (Agawa et ul., 1991). Tryptophan fluorescence and leakage measurements proved that the ionization state of the glutamic acid residues plays a considerable role in the interaction of some 20 residue peptides with POPC large unilamellar vesicle membranes (Rafalski et al., I99 I ). The duration of the antidiuretic hormone, Arg8-vasopressin was increasing by the encapsulation in PG liposomes (Woodle et al., 1992). It has been suggested that poiymyxin B can induce ion-conducting pathways in membranes from negatively charged phospholipids (Schroder et al., 1992). Basic peptides bind to acidic lipids in membranes, the arginine peptides bind more strongly than the lysine peptides (Mosior and McLaughlin, 1992). In the study of the effect of amphipathic peptides on the fusion of egg yolk PC:egg yolk PA (3:l) it was established that the charge interaction between the basic peptides and acidic phospholipids is an important factor to induce the perturbation and fusion of the bilayer (Lee et al., 1992b).

128

T. CSERHATIand M. SZ&YI

Enzymes

PS and PI inhibited the phosphatase activity of the red cell membrane calcium pump whereas PC was ineffective. The results are consistent with the idea that acidic phospholipids stabilize an enzyme-Ca’+ complex lacking phosphata~ activity (Rossi and Caride, 1991). PE stimulated the activity of the soluble phosphat~date phosphohydrolase from rat liver, whereas PG, PS and PI were inhibitory (Humble and Berglund, 1991). The hydrolysis of mixed DLinPE and POPC dispersions by porcine phospholipase A, has been studied using multilamellar and supercritical large unilamellar vesicles. In mixtures with defect structures, PE appears to be more susceptible to the enzyme than PC (Sen et al., 1991). Negative charged phospholipid analogues were more potent inhibitors of porcine pancreatic phospholipase A, than the zwitterionic ones (Ransac et al., 1992). An enzyme was isolated from the culture su~rnatant of Cytop~aga sp. that had a cleavage specificity of a phospholipase C. It hydrolysed PI but did not act on PC (Jager et al., 1991). PE, PG, DMPC, egg yolk PC, PI, Ps, DPPC and DOPC induced activation of phosphatidylinositol-specific phospholipase C in rat liver plasma membranes, SM was ineffective. PE and egg yolk PC were observed to be most effective in phospholipase C activation (Momchilova-Pankova et al., 1991). Protein kinase c and three other cytoplasmic proteins (64, 32 and 22 kDa) showed great selectivity for membranes containing PE rather than PC as the neutral phospholipid (Bazzi ef al,, 1992). Interaction of PIP, with the various protein kinase c isozymes was greatly facilitated in the presence of Mg2+ or Cal+ (Huang and Huang, 1991). Two subtypes of protein kinase c were isolated from bovine heart. In the presence of Istearoyl-2-arachidonylglycerol, the two kinases were maximally stimulated by PS. Other phospholipids, such as lyso-PS, PI, PA and CL were less effective. PE, PC and SM were ineffective (Allen and Katz, 1991). PIP:! as well as diacylglycerol activate protein kinase c in the presence of calcium and PS. It is possible that both 4- and 5-phosphate are engaged in the PIP,-Ca-enzyme complex (Chauhan et al., 1991). A Ca’+-independent but 12-~-tetradecanoyl phorbol ester-phospholipid-activated protein kinase was isolated from rat embryo fibroblast 3Y 1 cells. This enzyme requires PA for activation, but CL, PE, PS, and diacylglycerol are less effective and PC and PI are ineffective (Uchida et al., 1991). PA, PI and PS have a negligible effect on intrinsic caseine kinase I activity. Phosphatidylinositol 4,5-biphosphate showed a higher inhibitory effect than monophosphate did (Brockman and Anderson, 1991). Mitochondrial creatine kinase (EC2. 7.3.2) interacted with anionic phospholipids, the effect was higher with CL than with PI and DOPS (Rojo et al., 1991). Anionic liposomes composed of MPG, DOPG, CL in PC modify the activity of cytochrome e (Cheddar and

Tollin, 1992). The binding of cytochrome c to negatively charged lipid surfaces (DMPG, OPG, DOPC) shifts its conformational and coordination equilibria (Heimburg et al., 1991). Small unilamellar vesicles of egg yolk, PC influenced the electron transfer capacity of tuna heart cytochrome c (type XI). The activity depended on the ration of negatively charged dihexadecylphosphate incorporated into the liposomes (Cheddar and Toll, 1991). The activity of D-fructose dehydrogenase isolated from Giuconobacter sp. was enhanced by the incorporation in charged phospholipids (Kheirolomoom et al., 1991b). The membranebound respiratory enzyme D-lactate dehydrogenase of Escherichia coli is protected from trypsin digestion to a larger extent when it interacts with PG than with PC vesicles. Trp 243, 340 and 361 are exposed to the lipid phase, while Trp 384,407 and 567 are accessible to the external aqueous phase (Truong et al., 1991). A positive correlation was found between the number of negative charges on the phospholipid (PIP2 > PIP > PA = PC > PC) and the potency of their pyrene-labelled analogues to act as quantum acceptors in fluorescence energy transfer from the tryptophan residues of the (Ca*+ + Mg2+)-ATPase (Verbist et al., 1991). Acidic phospholipids, like PS, stimulated the transport properties of Ca*+-pumping ATPases from carrot (Daucus carota cv Danvers) tissue culture cells (Hsieh et al., 1991). PS specifically activated the vanadate-sensitive ATPase from chromaffin granule membranes, whereas PG, PC, PI, PE and lysophospholipids had no effect (Moriyama et al., 1991a). PS plus Ca2+ markedly activated the porcine 80-kDa diacylglycerol kinase. The results demonstrated that Ca’+ plays a key role in the regulation of the action of the enzyme by controlling its interaction with membrane phospholipids (Sakane et al., 1991). The reaction velocities of the microbial lipasejacyltransferase isolated from Vibrio sp. were higher with monolayers of DLPC than with PG and PE (Hilton and Buckley. 1991). r>-3-Hydroxybutirate dehydrogenase, an innermitochondrial enzyme is activated by phospholipids. A positive charge on the polar head is required for the activation but it must be at the surface of lipid vesicles (Nasser et al., 1991). ~ardiolipin synthase purified from rat liver mito~hondrial membranes requires interaction with several molecules of PE and at least I molecule of CL for full enzymatic activity (Schlame and Hostetler, 1991). Acidic phospholipid-containing vesicles stimulate the activity of purified placental glucosylceramidase (Vaccaro et al., 1992). Acidic phospholipids were necessary for the reconstitution of the transport activity of the branched-chain amino acid transport system of Lactococcus iactis (Veld et al., 1992). Incorporation of PE and PG into the membranes stimulates the activity of ceramide”phosphorylethanolamine transferase activity in rat liver plasma membranes, whereas SM and PS suppress the activity (Nikolova et al., 1992).

Interaction of phospholipids Other proteins Equilibrium dialysis and Trp fluorescence measurements were used to examine the phospholipid dependency of calcium binding of three proteins (Mol wt = 64, 32 and 22 kDa) isolated from bovine brain. The binding depended on the type of head group (PC or PS) (Bazzi and Nelsestuen, 1991a). The proteins induced extensive clustering of acidic phospholipids (PA or PC) in the membranes (Bazzi and Nelsestuen, 1991 b) and the binding involved possibly 8-10 calcium ions (Bazzi and Nelsestuen, 1991~). ADPribosylation factor purified from bovine brain cytosol binds to the anionic phospholipids Ps, PI and CL but not to the neutral PC (Walker et al., 1992). Asialofetuin is a glycoprotein molecule possessing triantennary galactose terminated sugar chains. PA : PC : CH liposomes containing asialofetuin were added to freshly isolated hepatocyte suspensions. The binding was found to increase with increasing PA content of liposomes. It was suggested that the binding mechanism may involve interactions other than those of electrostatic nature (Hara et al., 1991). Turbidimetric and fluorometric methods were used to assess the effect of proteins from Taiwan cobra (Nu& nuja utru) venom on the fusion of SM vesicles. The proteins caused fusion at temperatures slightly above the gel to liquid crystalline phase transition. The interaction is not likely due to the nonspecific hydrophobic interaction between the protein and the lipid molecule. The substitution of Ala- 17 by Glu- 17 enhances the strength of interaction proving its hydrophobic character (Chien ef al., 1991). High-M, kininogen and factor XII/factor XIIa bind to negatively charged phospholipids only. The binding of high-Mr kininogen was not affected by the presence of zinc ions, while the amount of bound purified cc-factor XIIa could be increased 4-5-fold in the presence of zinc ions (Schousboe and Halkier, 1991). Anionic phospholipid species such as PS are necessary for the expression of the anticoagulant function of activated protein C (Freysinnet et al., 1991). It has been indicated that human factor V possesses a PS-specific binding site within the C2 domain of the light chain (Ortel et al., 1992). Human platelet P-23 is a talin-like actin binding protein. Its interaction with lipid bilayers (DMPC, DMPG, DMPS) is greatly enhanced in the presence of charged lipids. The electrostatic nature of the interaction was concluded from differential scanning calorimetric and FTIR measurements (Heise et al., 1991). The application of liposomes as carriers of antigens and adjuvants has recently been reviewed and the importance of liposomal charge was emphasized (Alving, 1991). pH sensitive liposomes have been prepared from DOPE, DOPC, PS, CH and 1,2-dioleoyl-sn-succinyl glycerol. Ovalbumin containing liposomes could sensitize target cells to lysis by class I MHC-restricted ovalbumin-specific cytotoxic T lymphocytes (Reddy et al., 1991). Negatively charged liposomes efficiently bind to and are rapidly

with proteins and peptides

129

endocytosed by macrophages (Utsugi et al., 1991). Some hemolysis of erythrocytes in vitro occurred on interaction with cationic liposomes (PC or DPPC) where the positive charge was contributed 2,3-dioctadecenyl-oxypropyl-N,N,N-trimethylby ammonium chloride or stearylamine, but not 2,3-dihexadecyloxyl-propyl-N,N,N-trimethylammoniumchloride (Senior et aI., 1991a). Two mammalian cell lines, an African green monkey kidney cell line and a murine macrophage-like cell line recognized negatively charged phospholipids incorporated into egg PC: CL (2: 1) liposomes (Lee et al., 1992a). pH sensitive liposomes composed of DOPE, DOPC, DOSG, PS and CL provide a useful means to deliver a soluble antigen to dendritic cells (Nair et al., 1992). Monomethoxypoly(ethylene glycol) was covalently coupled to small unilamellar vesicles via the free amine group of DPPA incorporated at 20 mol% of total phospholipid, into a rigid liposomal bilayer composed of DSPC and equimolar CL. Modified liposomes appear to adsorb plasma components more slowly than liposomes without the polymer. Hydrophilicity increases the half-life of liposomes in mice (Senior et al., 1991b). Two rabbit lung calcium-dependent phospholipid-binding proteins (36 and 33 kDa bind to the DOPC-PC monolayer but not to DOPC monolayer (Tsao et al., 1991). Lung surfactant proteins SP-B and SP-C induce the formation of DPPC-PC monolayers. The insertion of phospholipid from phospholipid vesicles into the protein-containing monolayers was dependent on the presence of (divalent) cations (Oosterlaken-Dijkstrehuis et al., 1991a). Pulmonary surfactant protein A induces a rapid Ca*+-dependent aggregation of DPPCjPG 7: 3 vesicles. The vesicle aggregation is mediated by Ca*+-induced interactions between carbohydrate-binding domains and oligosaccharide moieties of the surfactant protein (Haagsman et al., 1991). Epithelial Na+ channels isolated from toads (Bufo murinus) were reconstituted into planar PC bilayer membranes. Both Ca’+ and pH strongly influenced the channel-mediated current (Siqieira-Branco and Varanda, 1991). The systemic lupus erythematosus sera gave positive results for many phospholipids tested by ELISA. The order of phospholipid reactivity was PA > PS > PI > CL > PC > PC > PE. The sera of healthy subjects gave much lower values. Antiphospholipid autoantibodies reacted particularly with anionic phospholipids (Maneta-Peyret et al., 1991). It was established that the specific interactions between the aminophospholipids of the inner leaflet of the bilayer and the cytoskeleton, particularly spectrin are not involved in the maintenance of an asymmetric distribution of phospholipids in erythrocytes (Pradhan et al., 1991). Spectrin is a key component of the red cell skeleton responsible for cell elasticity and stability. It induces leakage from PS/DOPC vesicles but has negligible leakage from PSjCH and PSjPOPE vesicles (Subbarao et at., 1991). Spectrin also influences temperature, half-width and enthalpy of phase

130

T. CSERHATI and M.

transitions in DMPE/DMPC mixtures and this effect was dependent on the DMPE to DPMC weight ratio (Hendrich et al., 1991). Apocytochrome c, the hemefree precursor of cytochrome c interacted more strongly with acidic DMPG than with zwitterionic DMPC. In complexes of lower lipid to protein ratios (~40: l), infrared spectra are indicative of an extended, intermolecularly hydrogen-bonded P-sheet structure (Muga et al., 1991). SecA is a peripheral cytoplasmic membrane protein, which plays essential roles in the translocation of secretory proteins across the cytoplasmic membrane of Escherichia coli. It was suggested that SecA directly interacts with PG and CL but not with PE (Shinkai et al., 1991). It was demonstrated that anionic phospholipids by virtue of their negative head group charge are involved in the translocation of the precursor of the pore protein PhoE across the Escherichia coli inner membrane and besides a negative charge no other structural head group requirements are involved in the translocation stimulatory effect (Kusters et al., 1991). Purified placental annexins VI and IV bind to PS, PI and PE in the presence of calcium. Neither annexin VI or IV bind to PI bisphosphate and PC even at high concentration of calcium (Edwards and Crumpton, 1991). The interaction of the M 13 major coat protein in the a-oligomeric form with specifically deuterated DOPC, OPE and DOPG headgroups has been studied using ‘H NMR methods. The differences between the observed changes in the quadrupolar splitting of headgroups are probably due to the differences in hydrogen bonding capabilities and differences in charge distribution of the headgroups used. The changes induced by the Ml3 coat protein on the lipid headgroups may be due to a charge induced effect (Sanders et al., 1991). The conversion of the positively charged His-440 to a neutral cysteine in the bacterial toxin colicin El modifies its channel forming properties of asolectin bilayers (Abrams et al., 1991). It was found that the B-subunit of cholera toxin is able to induce ionic channels in PS: PC : CH 1: 1: 1 bilayers at low pH whereas the A subunit is not able to do it (Krasilnikov et al., 1991). Unitary currents through cGMP-dependent channels of retinal rods were observed following incorporation into planar lipid bilayers consisting of PE: PS 7: 3 wjw (Ildefonse and Bennett, 1991). Ten to twenty pg/ml of CL augmented the release of tumour necrosis factor from peripheral macrophages while 40 pg/ml completely suppressed the release. PS was less active and PC was inactive (Yui and Yamazaki, 1991). Proline residues in transmembrane helices may have one or more structural and/or dynamic roles, with the function of a particular Pro mediated by its local environment (i.e. within the nonpolar bilayer) and by the requirements of its parent membrane protein. These roles stem from the capacity of Pro to exert characteristic structural, electronic and conformational effects (Williams and Deber, 1991). Chicken muscle CapZ, a member of the capping protein

SZ~GYI

family of actin-binding proteins, binds to the barbed end of actin filaments and nucleates actin polymerization. Phosphatidylinositol 4-monophosphate is nearly as effective as phosphatidylinositol4,5-biphosphate at inhibiting CapZ, and other anionic phospholipids including PI, PS, PA and PG can also inhibit the capping activity of CapZ, albeit at higher phospholipid concentrations. No activity was seen with the neutral phospholipids PC and PE (Heiss and Cooper, 1991). A 23 kDa protein isolated from rat epididymal secretions showed selective affinity for PE with lower affinity towards PI and PC (Jones and Hall, 1991). The fusion of hemagglutinin of influenza strain X31 with PC:SM:CH 1: I:2 monolayers occurred only at low PH (Burger et af., 1991 b). Calphobindinan anticoagulant protein isolated from human placenta is a member of the annexin family. The number of calphobindin-II capable of binding to 80% PC and 20% PS vesicles at 0.3 mM Cal+ decreased to about l/2 in the presence of Ca’+ of more than 1 mM (Yoshizaki et al., 1991). The procoagulant effect of platelets and platelet-derived microparticles is mediated by calcium-induced exposure of anionic phosphohpids (Thiagarajan and Tait, 1991). Deprotonated head groups like PCs influenced the mitochondrial Ca*+ transport and membrane potential while partially protonated head groups like PEs are essentially inactive (Rustenbeck et al., 1991). HYDROPHOBIC AND

HYDROPHILIC

INTERACTIONS

Peptides 2H NMR was used to study the interaction of amphiphilic model peptides with membranes consisting of DOPS deuterated either at the p-position of the serine moiety or at the I l-position of the acyl chains. The peptides are derived from the sequences H-Ala-Met-Leu-Trp-Ala-OH and H-Arg-Met-LeuTrp-Ala-OH. 2H spin-lattice relaxation time measurements demonstrate a decrease of the rates of motion of both head group and acyl chains of DOPS in the presence of the peptides. Peptides modified head group and acyl chain order and dynamics (De Kroon et ul., 1991b). Circular dichroism, fluorescence spec“P and D NMR proved that the cyclic troscopy, peptide ( + )o-Phe’-Cys’-Phe’-D-Trp”-( + )Ly?-Thr6Cys7-Thr(ol)8 binds to lipid membranes by an electrostatic/hydrophobic mechanism (Beschiaschvili and Seelig, 1991). Angiotensins are biologically active peptides able to affect smooth muscle motorics. Both hydrophobic and hydrophilic forces are involved in the interaction of angiotensins with egg PC: CL (4: 1 w/w) membrane (Hianik and Laputkova, 1991). A 20-residue peptide corresponding to the amino terminal of the HA2 subunit of the influenza virus hemagglutinin protein interacted with phospholipid vesicles in the order PS > PE > PC. The tryptophan residues are at or near the hydrocarbon-polar interface (Clague et al., 1991). The study of the fusion of egg PC vesicles induced by peptides of hemagglutinin of

Interaction of phospholipids with proteins and peptides influenza virus suggests that the amphiphilic peptides become more hydrophobic by neutralization due to the protonation of the carboxyl groups or deprotonation of the lysil amino groups, aggregate the vesicles together, and interact strongly with the lipid bilayers. The fusion capacity of anionic and cationic peptides depended differently on the pH of the environment (Murata et al., 1992). The rate of binding of melittin to phospholipid unilamellar vesicles depends on the degree of saturation of the lipid acyl chain and on the net electric charge of polar head groups (Sekharam et al., 1991). Adjacent bilayers of DPPG are bridged by tetramers of melittin through electrostatic interactions inducing surface charge neutralization and partial dehydration of complexes. The hydrophobicity of the peptide is a key factor in the modulation of the gel to liquidcrystalline phase transition and in its insertion in the fluid lipid matrix (Lafleur et aZ., 1991). A new model has been proposed for the easier understanding of peptide-lipid interactions. The general idea was that a peptide, depending on its nature, will accept a specific location in the membrane, where it exerts an effect that depends on its differential contributions to the headgroup region and the hydrophobic volume. The interaction of the hydrophilic melittin and the hydrophobic gramicidin is explained in the terms of the model (Tournois and Kruijff, 1991). The rate of transition of gramicidin from a nonchannel to a channel form depended on the acyl chain composition of the phospholipids and on the type of head group of phospholipids (Cox ef al., 1992). Synthetic peptides corresponding to human follicle stimulating hormone (hFSH)-#?-(l-15) and hFSH-fi-(51-65) in2:l or duce uptake of 45Ca ‘+ by DOPC:CH DPPC:CH 2: 1 (molar ratio) liposomes. Peptides form transmembrane channels due to their possible amphiphilic a-helix structures (predominantly hydrophilic surface on one side of each of the peptides and a hydrophobic surface on the other side) (Grass0 ef al., 1991). The involvement of both hydrophobic and hydrophilic forces as well as that of conformational changes in the peptide-membrane interactions has recently been emphasized (Schwyzer, 1991). Basic amphipathic a -helical peptides with a long alkyl chain bind to lipid bilayer liposomes. Both the alkyl chain and the hydrophobic part of the a-helix in the peptide interact with the hydrophobic part of the membrane by penetration. The charge interaction between the hydrophilic part of the peptides and the phospholipid head groups helps preferentially their interaction (Kate et a/., 1991). The conformation of synthetic human growth hormone-releasing factor fragment (l-29) was different in the presence and absence of DMPG. It was supposed that the hydrophobic surface of the peptide bounded the alkyl chains of DMPG by hydrophobic interaction, whereas the acidic polar head groups interacted with the basic amino groups of peptide. PS and ganglioside also

131

affected conformation, DMPC was ineffective (Honda et al., 1991a,c). Tachyplesin I, isolated from the hemocytes of Tachypleus tridentatus is a broadspectrum antimicrobial peptide. It increases the permeability of phospholipid vesicles in the order PG > PS > PC, The unique Trp-2 residue of the peptide is located in the hydrophobic environment of the PG bilayer (Matsuzaki et al., 199la). Prothrombin and prethrombin I adsorbed preferentially to acidic phospholipids, while fragment I preferred a neutral membrane containing only PC. Prothrombin and prethrombin are acidic peptides, and either a specific interaction or possibly a hydrophobic interaction must be invoked to account for preferentially binding of these peptides to acidic phospholipid membranes (Tendian et al., 1991). A theoretical stereochemical analysis revealed the importance of both hydrophilic and hydrophobic forces in the interaction of signal peptide with phospholipids (Kajava et al., 1991). Pse~do~o~~ exotoxin A is a single polypeptide chain comprising 613 amino acids. It induces vesicle permeabilization and produces vesicle aggregation. The results suggest that the binding is initiated by electrostatic interactions, and a stretch of positively charged residues is involved in the binding. This electrostatic interaction orients the hydrophobic substructure of polypeptide, that penetrates into the lipid hydrophobic core (Menestrina et al., 1991). The N-terminal fragment of the adrenodoxin precursor formed an r-helical structure in the solution containing acidic liposomes. The change in lipophilicity also influenced the interaction (Aoyagi et al., 1992). Enzymes The activation of protein kinase c enzymes has been recently reviewed. The reversible protein kinase c interaction requires acidic phospholipid with no strong preference for a particular head group. The irreversible interactions produce surface pressure changes consistent with protein penetration into the hydrocarbon region of the membrane (Nelsestuen and Bazzi, 1991). The binding of pig pancreatic phospholipase A, to the lipid interface occurs through ionic interactions and is further promoted by hydrophobic interactions which probably occur along a face of the enzyme, with a hydrophobic collar and a ring of cationic residues, through which the catalytic site is accessible to substrate molecules in the bilayer (Ramirez and Jain, 1991). The hydrolysing activity of hepatic lipase (EC 3.1.1.32) depended both on the type of head group and on the length of fatty acid chain as determined by the monolayer technique (Thuren et al., 1991). The activity of purified sarcosine dehydrogenase from P~e~do~o~a$ putida was determined in multilamellar and small unilamellar vesicles. The magnitude of activation by DPPC, which has the longer aliphatic chains, was less than that by DMPC. In the cases of DMPA and DMPG, the magnitude of activation

132

T. CSERHKTI and M. Sziicvr

were higher than that of DMPC (Kheirolomoom et al., 1991a). The [H +]ATPase purified from corn root plasma membrane can functionally insert into bilayer from PC: PE:PG or PC: PE: PI, due to the presence of both hydrophobic defects promoted by PE. and negatively charged phospholipids (Simon-Plas et al., 1991). The ATPase solubilized from plasma membranes of mung bean (Vigna radiata L.) was reconstituted in liposomes. Both H +-pumping and the hydrolysis of ATP by the plasma membrane ATPase are strongly affected by the polar head group and composition of the fatty acyl chain of phospholipids (Kasamo and Yamanishi, 1991). Progesterone 5areductase was partially purified from gastric mucosa microsomes of guinea pigs. Synthetic IysoPC and 1ysoPE differing in acyl chain length stimulated the activity of the enzyme, the optimal fatty chains being of 12 to 16 carbon length. LysoPA, 1ysoPG and IysoPS greatly inhibited Sa-reductase activity (Ichihara and Tanaka, 1991). The lysozyme-induced fusion of PS vesicles is pH dependent and results from the penetration of enzyme into the hydrophobic core of the bilayer (Arnold et al., 1992). Other proteins Reaction center protein from the photosynthetic purple bacteria Rhodobacter sphaeroides was incorporated into PC vesicles. Both hydrophobic and hydrophilic interactions between the protein and PC were observed. The lipid environment modified electron transfer (Marbti, 1991). Bovine rhodopsin was recombined with various phospholipids (PC, PE, PS) and the formation of metarhodopsins MI and MI1 by an actinic flash was studied. Phospholipids containing unsaturated acyl chains were capable of full native-like MI1 production. The presence of PE or PS headgroups increased the amount of MI1 produced (Gibson and Brown, 1991). Both hydrophobic and hydrophilic interactions influence the protein-catalyzed transfer of alkenylacyl-. alkylacylor diacyl-glycerophosphocholines in unilamellar bilayer vesicles (Szolderits et al., 1991). Surface tension measurements in a pulsating bubble surfactometer were used to study the interaction of synthetic surfactant protein B and C peptides with DPPC: PG: PA (68 : 22 : 9 w/w) and to determine the effect of serum on the surface activity. A number of specific surface domains, including both amphipathic and hydrophobic segments, may be required for resistance of surfactant dispersions to inactivation with serum. Calcium enhanced the resistance to inhibition (Amirkhanian et al., 1991). The interaction of a family of synthetic peptides based on the native human pulmonary surfactant protein B with lipid dispersions (DPPC : egg PG : palmitic acid 68 : 22 : 10 w/w) was determined. The results indicate that electrostatic interactions and hydrophobicity are important factors in determining optimal structure and function of surfactant peptides in lipid dispersions (Bruni et al., 1991). ‘251-labelled pulmonary surfac-

tant protein A bound PC and SM, it was specially strong in binding DPPC, but failed to bind OG, PI, PE and PS. Labelled protein also exhibited string binding to DSPC, but weak binding to DMPC, PLinPC and DLinPC (Kuroki and Akino, 1991a). The interaction of non-enveloped plant viruses tobacco mosaic virus and cowpea chlorotic mottle virus and of their coat proteins with DOPC and DOPA membranes was investigated. The aggregation of vesicles is a result of the electrostatic interactions between the viral material and vesicles surface, while the destabilization of membrane is a result of penetration or bilayer disruption by hydrophobic protein domains (Spruijt et al., 1991). The low-pH driven interaction of diphtheria toxin is favoured by the presence of acidic phospholipids, without an apparent requirement for a particular class of negative lipids. The mutants crm 45 and crm 197 are capable of hydrophobic interaction already at neutral pH (Demel et al., 1991). The penetration of tetanus toxin in the lipid monolayer is pH dependent. It increases with lowering pH, it is facilitated by acidic phospholipids and by glycosphingolipid and it is mediated both by hydrophobic and electrostatic interactions as deduced from an analysis of the effect of ionic strength (Schiavo et al., 1991). An excellent review was published on phospholipid transfer proteins. It was stressed that both PC and PI transfer proteins appear to have distinct binding sites for the I- and 2-fatty-acyl chains. Owing to the different properties of these sites, both proteins can discriminate between molecular phospholipid species as well as between positional isomers of these species. Both electrostatic and hydrophobic requirements have to be met for a lipid molecule to be transferred (Wirtz, 1991). The interaction of cytolysins of bacterial (S. aureus cc-toxin, C. perfiingens O-toxin, E. coli x-hemolysin and B. thuringiensis a-toxin) and animal (perforin from mouse macrophage granules, sarcotoxin from the blood of injured insects and cytolysin from the nematocysts of sea anemone) origin with planar phospholipid membranes was studied. It was found that a common step in the action of these cytolysins is a conformational transition from hydrophilic to amphiphilic which renders them competent to bind to a cell membrane (Menestrina, 1991). The antitumour protein cx-sarcin interacts at neutral pH with acid phospholipid vesicles promoting their aggregation and fusion. Electrostatic and hydrophobic interactions are involved in the fusion of phospholipid vesicles (Gasset ef al., 199la). a-Sarcin was purified from the cultures of Aspergillus giganreus MDH 18894 and its interaction with DPMC, DMPG, DPPC and DPPG was studied by various physico-chemical methods. It was established that the water-soluble and hydrophilic ol-sarcin interacts with phospholipid bilayers by a combination of electrostatic and hydrophobic forces. The protein would initially adsorb to the charged polar head group of the phospholipids and further would partially

Interaction of phospholipids

penetrate the hydrophobic/hydrophilic interface of the bilayer to interact with a portion of the lipid hydrocarbon chains (Gasset et al., 1991b). Both the polarity of the head groups and the length of fatty acid chains influence the conformational state of major coat protein of bacteriophage Ml3 (Spruijt and Hemminga, 1991). The interaction of PI and PI/PC small uniiamellar vesicles with the intermediate filament protein vimentin and its isolated N-terminal polypeptide induces leakage. Both hydrophilic and hydrophobic forces are involved in the interaction (Horkovics-Kovats and Traub, 1991). A peripherally membrane-associated protein, SecA of Escherichia coli can insert into lipid monolayers, both electrostatic and hydrophobic forces are involved in the inter action (Breukink et al., 1992). NOT SPECIFIED

INTERACTIONS

Peptides

Colicin El is one of a group of bactericidal proteins which exerts its lethal action by forming an ion channel in the cytoplasmic membrane. The 178residue thermolytic COOH-terminal peptide of colicin El was reconstituted into DMPC liposomes. FTIr measurements suggested that the peptide showed a predominantly cc-helical structure in bounded state (Rath et al., 1991). Deuterium NMR and freeze-fraction electron microscopy proved that melittin and [Ala-14]-melittin are organized as discrete aggregates that penetrate deeply into the DMPC bilayer. The possibility cannot be ruled out that the different kinetics of reversible miceliization between the two peptides may also have a contribution from different positioning between the aqueous and biiayer phase (Dempsey and Sternberg, 1991). A new high performance liquid chromatographic method has been developed to examine the conformational transition of gramicidin A in PC or lyso-PC model membranes. The vesicles containing gramicidin A were injected on an Ultrastyragel 1OOOAcolumn and eluted with tetrahydrofuran. The monomer and dimer forms of gramicidin A (liberated from the disrupted vesicles) can be separately determined because the dimer-monomer transition in tetrahydrofuran is extremely low as compared to the elution time (Bano et al., 1991). The structure of gramicidin channels in phosphohpid bilayers has been defined more accurately using X-ray diffraction (Katsaras et al., 1992) by circular dichroism (Koeppe et al., 1992) and conductivity measurements (Cifu et al., 1992). Solid-state *H NMR spectroscopy has been employed to study the channel formation of gramicidin A in unoriented DMPC multilayers. Helix sense of gramicidin A was found to be right-handed (Prosser et al., 1991). An ultrarapid filtration method has been developed for the measurements of water and solute ~rmeability of synthetic and biological vesicles. Gramicidin increased the permeability of egg PC:egg PA 9: 1 mol/mol liposomes (Martial

with proteins and peptides

133

and Ripoche, 1991). The perturbation of the phase behavior of DMPC by gramicidin was found to be relatively insensitive to gramicidin conformation (Morrow et al., 1991). A 30-amino acid peptide, based upon a Glu-Ala-Leu-Ala motive, was synthesized. Attenuated total reflection infrared spectroscopy proved an increase to 100% a-helix after interaction with POPC. a-Helices are oriented parallel to the hydrocarbon chains of the lipid (Goormaghtigh et al., 199lb). The interaction of three synthetic analogues with an amino acid sequence corresponding influenza virus hemagglutinin was studied in DOPC, DOPE, SM and CH monolayers, A defined tertiary structure or orientation of the a-helical peptide may be essential for its membrane perturbing activity (Burger ef al., 1991a). The presequence of the F’-ATPase p-subunit precursor binds to POPCjPOPEjPOPG 40: 24: 36 (mol%) small unilammellar vesicles (Hoyt er al., 1991). The interaction with DMPG of the ore-foxing domain of cohcin A modifies the a-helix content of the peptide (Goormaghtigh et al., 199la). The highest value of incorporation of thymostimulin, an immunoactive hormone, was reached by liposomes composed of DPPC: DMPC 1: 1 mol (Panic0 et al., 1992). The use of liposomes in ophthalmology as carriers of peptide drugs has been recently reviewed (Niesman, 1992). ~-Acetyl-muramyl-L-alanyl-D-isog~utamy~-L-alany~2-( 1’,2’-dipalmitoyl-sn-glycero-3’-phosphorylethylamide and N-hexadecanoyl-S-(2(R)-3-didodecanoyloxypropylf-L-cyteinyl-L-alanyl-~-isoglutaminyl-glycyl-taurine sodium salt showed enhanced tumoricidal activation of monocytes and macrophages when encapsulated in DOPS and POPC liposomes (Utsugi et al., 1991), the ideal liposome carrier consisted of PC and PS in a 7:3 mofar ratio (Nii et al., 1991). A peptide derived from the hemagglutinin protein of influenza virus was encapsulated in egg yolk purified PC liposomes. The liposomes containing the peptide exhibit a T-dependent carrier effect for a T-independent Ag (Garcon and Six, 1991). Liposome-encapsulated muramyl tripeptide phosphatidylethanolamine has been successfully applied in the treatment of experimental Klebs~ef~a~~earno~a~e infection in mice (Melissen ef al., 1992). Muramyl tripeptide phosphatidylethanolamine encapsulated in liposomes stimulates monocyte production of tumour necrosis factor and interleukin-1 in vitro (Maeda e6 a/., 1991). Liposomal amphotericin B was less toxic to the host and had higher therapeutic capability than dispersions of the free drug (Kreuter, 1991). A 24-residue amphipathic r-helical peptide mixed with DPPC was effective as lung surfactant (McLean et al., 1992). Enzymes

Both calcium and phorbol ester induced the association of protein kinase c with bovine brain PS/bovine liver PC liposomes (Irita et al., 1991). DPPC inhibited protein kinase c competitively with respect to PS, and noncompetitively with respect to CaCI, (Shoji et al.,

134

T. CSERHATIand M. Sziicvt

1991). The activation of protein kinase c by PS involves binding of PS monomers to interacting sites on the enzyme (Sandermann and Duncan, 1991). PS is needed for the phosphorylation of brush border myosin I from chicken intestine by chicken intestinal epithelial cell protein kinase c (Swanjun~-Collins and Collins, 1992). Melittin and phosphoiipase A, form ternary complexes with DMPC as demonstrated by circular dichroism measurements (Nishiya, 1991). Escherichia coli outer-membrane phospholipase can be reconstituted in egg PC/egg PG (80/20) vesicles. The enzyme can be activated by the addition of the membrane perturbing peptides polymyxin B, melittin or cardiotoxin (Horrevoets et al., 1991). Membrane active peptides considerably modify the activity of phospholipases A,, C and D towards PC small unilamellar vesicles (Rao, 1992). The presence of ascorbate oxidase significantly reduced the volume of DPPC liposomes and accelerated liposome ageing and fusion (Dini et al., 1991). The presence of phosphatidylethanol in the lipid bilayer reduced the NA” /K+ ATPase activation induced by ethanol and enhanced 5’-nucleotidase activity (Omodeo-Sale et al., 1991). The Hi-ATPase of Escherichia coli was reconstituted with egg yolk PC, PC:PS 2: 1 or 1: 1 w/w, soybean PC (type II-S and type IV-S and E. coli phospholipids). ATP-dependent H + translocation was highest in liposomes reconstituted with soybean PC type II-S or E. coli phospholipids (Moriyama ef al.. 1991b). The malate carrier of barley (Hordeurn vulgare L.) mesophyll vacuoles were successfully r~onstituted in asolectin liposomes (Martinoia et al., 1991). Phosphatidylinositol 4-kinase (ATP:phosphatidylinositol 4-phosphotransferase, EC 2.7.1.67) was purified from Succharomyces cerevisiae. Glycerol gradient centrifugation studies showed that the enzyme was physically associated with Triton X-loo/PI micelles (Buxeda et al., 1991). Two isoforms of UDP-glucuronyltransferase were purified from rat liver (GT-1) and kidney (GT-2). I-Naphtol glucuronizing activity of GT-1 was increased 7.S-8-fold by lyso-PC, but the activity of GT-2 was increased only 3-3.6 fold. The transferase activity of GT-1 toward 4-methylum~IIiferone was increased 2-2.5 fold by DLPC, but that of GT-2 was reduced (Yokota et al., 1991). Beef heart cytochrome c oxidase could be functionally reconstituted in liposomes consisting of macrocyclic tetraethers with two polar heads linked by two hydrophobic Cd0phytanyl chain. These unusual phospholipids are present in the membrane of Sulfolobus acidocaldarius, a thermophilic archaebacterium (Elferink et al., 1992). Horse heart apocytichrome c interacted with POPS small unilamellar vesicles as determined by time-resolved fluorescence study of the single tryptophan residue (Trp-59) (Vincent and Gallay, 1991). Cytochrome c oxidase and cytochrome c reductase have been successfully reconstituted into soybean phospholipid vesicles (Capitanio et al., 1991). The adsorption of cytochrome c molecules at an electrically neutral PC

membrane influences the processes of electron transfer (Salamon and Tollin, 1991). A system mimicking one of the key events in natural photosynthesis has been constructed. The negatively charged large unilameliar vesicle system contained a membrane-bound photosensitizer (chlorophyll), a reduced redox protein (cytochrome c) in the inner aqueous compartment, an oxidized redox protein (fe~~oxin) in the outer aqueous compartment, and propylene diquat as a mediator (Zhao and Tollin, 1991a,b). Functional tonoplast H +-ATPase isolated from mung bean (Vigna rudiata L.) was successfully reconstituted in a mixture of soybean phospholipids (asolectin) (Kasamo et al., 1991). The incorporation of phospholipids that induce membrane fluidization such as DOPC, egg yolk PC, PI, Ps and PE was accompanied by an elevation of the activity of acyl-CoA: l-acyl-snglycero-3-phosphocholine 0-acyl-transferase in rat liver piasma membranes (Momchilova et al., 1991). The presence of phosphoIipids other than PC may profoundly alter both the physical properties of the lipoprotein particles and their reactivity with lecithin-cholesterol acyltransferase (Bonomo et al., 1991). Catalase and/or superoxide dismutase entrapped in DPPC : CL : stearylamine 14: 7 : 4 molar ratio considerably decreased the pulmonary toxicity of bleomycin (Ledwozyw, 1991). Superoxide dismutase entrapped in PC: CL : stearylamine 80: 11.4: 22.8 mol/mol liposomes showed anticonv&ant effect in amygdaloid-kindled rats (Yokoyama et al., 1992). Ot~ler proteins

A new miniaturized micro-fluorescence film balance was developed to monitor protein-containing lipid monolayer spread from vesicle suspension. The method uses a movable epifluorescence microscope over the monolayer (Heyn et al., 1991). The active form of adenotin, a low affinity adenosine binding protein, has been successfully reconstituted in PC vesicles (Hutchinson et al., 1991). T-tube microsomes isolated from the skeletal muscle from the hind legs and back of New Zealand white rabbits formed two populations of dihydropyridine-sensitive calcium channels in planar lipid bilayers consisting of PO PS:POPE 1: 1 ~Mejia-Alvarez et al., 1991). Isolated rat liver gap junction membrane proteins form channels in asolectin bilayers (Campos-de-Carvalho et al., 1991). Rabbit renal brush-border membranes were fused to planar lipid bilayers consisting of bovine brain PE: DPhPC 8 : 2 w/w and a large conductance channel was commonly observed (Zweifach et al., 1991). The heavy chain of tetanus toxin increased the permeability of liposomes composed of PC and PS (Hogy et al., 1992). The IP, receptor of aortic smooth muscle forms channels in soybean lipid planar biiayers. The incorporation of the receptor triggered Cat+ release (MayrIeitner et al., 1991). The ATP-sensitive K + channels isolated from aortic smooth muscle were successfully incorporated into

Interaction of phospholipids with proteins and peptides planar lipid bilayers consisting of PE:PS 4: 5 w/w (Kovacs and Nelson, 1991). The steps in the purification of a K+ channel protein of the sarcoplasmic reticulum was assayed by inserting the preparation in a planar lipid bilayer system (asolectin) and by measuring the channel conductance (Ide et al., 1991). Gpl20, the coat protein of human immunodeficiency virus equally forms channels in PE: PS 1: 1 and DPhPC bilayers containing CD4 (Tosteson et al., 1991). Platelet membrane glycoprotein IIb-IIIa complex forms Ca *+-channels in PC:PS 4: 1 bilayers (Fujimoto et al., 1991). Anion channels isolated from sheep tracheal epithelium have been successfully incorporated into PE: PS (70: 30%) planar bilayers (Alton ef al., 1991). The major intrinsic protein (MIP26) of bovine lens membranes forms channel in PE and CL planar lipid bilayers (Shen et al., 1991). Rabbit skeletal muscle transverse tubule membranes were fused with planar bilayers (PE : PS : CH, 1: 1: 0.2) and Ca channel forming capacity was studied (Ma et al., 1991; Mundina-Weilenmann et al., 1991). Activated S-endotoxin (CrylA(c)-55 kDa) isolated from Bacillus thuringiensis kurstaki strain EC2244 induces ion-leakage and water leakage in PC vesicles, brush-border membrane catalyzes these events (English et al., 1991). Low-conductance chloride channels have been isolated from skeletal muscle sarcoplasmic reticulum vesicles of the crayfish Astacus ffuoiulis. and was successfully incorporated into asolectin lipid bilayers (Proks et al., 1991). The Cl channels of shark rectal gland were successfully reconstituted in planar bilayers composed of PS : PE 1: 1 (Sansom and Carosi, 1992). The ion channels of the silkworm moth (Bombyx mori) antennae showed elementary conductances in azolectine bilayers (Yoshii et al., 1992). The antigen Fl, a protein of 17 kDa is produced by Persinia pestis. It causes permeability increase in lipid bilayer membranes (Rodrigues et al., 1992). Potassium channels isolated from the plasma membrane of rye roots were functionally reconstituted into POPE planar bilayers (White and Tester, 1992). Vacuolar ion channels were active after incorporation into PE or DPhPC planar bilayers (Klughammer et al., 1992). A protein isolated from the outer membrane of the acidophilic, chemolithotropic bacterium, Thiobacillus ferrooxiduns formed anionic channels in PE planar bilayers (Silva et al., 1992). Sealed unilamellar vesicles consisting of DMPC: CH : PPS : DPPE at molar ratios 54: 35: 10: 1 facilitate the binding of c(- and fir-subunits of G, to /3,-adrenoreceptor (Kurstjens et al., 199 I). The decrease of temperature or the increase of osmotic pressure caused the change of aggregation state of bacteriorhodopsin reconstituted in DMPC vesicles (Yamada and Ishizaka, 1991). B-G molecules purified with monoclonal antibodies exert an adjuvant effect on the production of alloantibodies to chicken class I (B-F) molecules, when the two are in the same PC liposome (Salomonsen et al., 1991). The reactivity of T cells is different to hen egg lysozyme

135

and PC-hen egg lysozyme conjugate in C57BL/6 mice (Jang et al., 1991). DPPC is taken up by the type of II alveolar cells of the perfused lung of male Sprague-Dawley rats in a manner linear with time (Moxley et al., 1991). Lung surfactant apoproteins B/C cause an orientational or conformational change in the carbonyl of DPPC as observed by ‘-‘C NMR (Salmon and Wiedmann, 1991). The deglycosylated pulmonary surfactant protein A can aggregate DPPC:egg PC: PG 9: 3 :2 w/w liposomes to some extent but it appears to be less than that of native SP-A. The oligosaccharide moieties of P-A may, in part, be involved in the activity of liposome aggregation (Kuroki and Akino, 1991b). Pulmonary surfactant proteins, SP-B and SP-C are directly responsible for the binding of lipid vesicles to the monolayer. By weight, the vesicle binding capacity of SP- is approximately 4 times that of SP-C (OosterlakenDijksterhuis et al., 1991b). Pulmonary surfactant proteins SP-A, SP-B and SP-C induce changes in the structure of simple phospholipid (PG, DPPC) mixtures (Williams et al., 1991). The phosphatidylcholine-specific transfer protein facilitates the incorporation of DPPC in the plasma membrane of Madin-Darby canine kidney cells (Zlatkine et d., 1991). The trapping of insulin in large unilamellar vesicles of DPPC, PC and CL was highly facilitated by the formation of transient membrane holes induced by sodium cholate and n-octyl p-D-glucopiranoside (Schubert et al., 1991). Protein z is a single-chain vitamin K-dependent glycoprotein that has been found in bovine and human plasma. The function of protein z is unknown. It was established that protein z bound to large phospholipid vesicles (25% PS, 75% PC) with a dissociation constant of 0.39 k 0.16 PM at a phospholipid protein ratio of 82 mol of phospholipid/mol of protein z at saturation. In the presence of protein z thrombin associated with phospholipid vesicles, whereas thrombin did not interact with phospholipid vesicles in the absence of protein z (Hogg and Stenflo, 1991). Rat and human blood serum induce aggregation of DPPCjPI liposomes at low serum protein concentrations, but the aggregate dissociate at higher serum protein concentration (Jones and Nicholas, 1991). The interaction between the purified major histocompatibility complex class II protein 1-E’ and a fluoresceinated peptide representing amino acids 89-104 of pigeon cytochrome was studied with 1-E’ reconstituted in DPPC : DOPC : CH (9: 1:2.7 mol ratio) vesicles. The complex formation can be described with first-order kinetics (Witt and McConnell, 1991). The classical class I MHC molecules differ in their mode of anchorage to the membrane lipid bilayer. H-2Db is anchored by a transmembrane peptide, while Qa-2 is anchored by a glycosylphosphatidylinositol anchor (Edidin and Stroynowski, 1991). Small unilamellar vesicles consisting of hydrogenated egg PC-CH showed 4-fold more accumulation of liver of male albino Wistar rats when

136

T.

CSERHATIand

30-stearyl glycyrrhizin was added to the liposomes (Tsuji et al., 1991). DLPC induced cell motility in caput and cauda sperm to zone-free hamster eggs (Graham et al., 1991). The encapsulation of histone, a nuclear protein, together with DNA into N-(atrimethylammonioacetyl)-didodecyl-D~giutamate : DLPC : DOPE I : 2 : 2 molar ratio liposomes increased the expression of ~-galactosidease activity by about 50% (Yagi et al., 1991). The neuronal growth-associated protein GAP-43 is expressed during axonal outgrowth and regeneration. t.-CL-Lysophosphatidylcholine mediates the delivery of anti-GAP-43 antibodies into cells (Shea et al., 1991). In a serum-free primary culture, membrane lipids, such as PE, PC or CH, effectively prolonged the survival of adult rat hepatocytes. The effect appears to be due to stabilization of the plasma membrane (Miyazaki et al., 1991). The CNBr fragments of human apoliprotein A-I form complexes with DMPC, the apoliprotein hehcat segments oriented parallel to the phospholipid acyl chains (Vanloo et at., 1991). Pig apoliprotein A-I interacts with PC and CL monolayers at trioleinsaline interface (Handa et af., 1992). A new electron paramagnetic resonance method has been developed to study the interaction of liposomes with leukocytes. The paramagnetic probe N-( l-oxy-2.2.6.6-tetramethyl-4-piperidinyl)-N-dimethyl-N-hydroxyethylammonium iodide was encapsulated into DPPC: DPPG (4 : 1) liposomes and the transfer of the probe to leukocytes isolated from fresh bovine blood was determined (Sentyurc ei al., 1991). A drug consisting of ~-acetylglucosaminyl-~-acetylmuramylL-a1anyi-D-isoglutamyl-L-alanyi-glyceryldipaImitate was incorporated into Iiposomes (POPC : DOPC 175: 75 w/w). The product showed marked anticancer effect in a phase clinical trial (Vosika e6 al., 1991). The presence of a phospholipid was essential for the retention of high activity of the human red cell glucose transporter. PC was nearly as effective as PS (Lundahl et al., 1991). A synthetic ether-linked phospholipid (I-O-octadecyl-2-O-methylglycerol phosphocholine) inhibited the growth of the KG-I acute myelogenous leukemic cells (Reed et al., 1991). The fluctuation and rotation of human growth hormonereleasing factor modified in the presence of DMPG (Honda et al., I991 a). t -palmitoyl-lysophosphatidylcholine was able to permeabilize sarcoplasmic reticulum vesicles (Teruel et al., 1991). DMPC and DMPG liposomes containing the hydrophobic synthetic recombinant protein R32NSl were phagocytosed by macrophages (Verma et al., 1991). The humoral response to bovine serum albumin either encapsulated in or surface-linked to DMPC:CH : DPPE (63 : 3 1:6 mol/mol) depended on the protein : lipid ration and on the type of formulation (Therien ef al., 1991). The strength of interaction of the I40/130/ 110 kDa protein complex of ~~as~~di~~ f~~ci~~r~~ with PC, PE, PS, PI and PG iiposomes did not depend on the head group characteristics of the phosphohpids (Sam-Yellowe and Perkins, 1991).

M.

SZ~GYI

Laminin, a large multi-domain glycoprotein of the extracellular matrix and bovine serum albumin interact with POPC and POPG (Kalb and Engel, 1991). The circulation half life in mice of various liposome formulations, such as SM:egg PC : CH : monosialogangiioside GM, 1:1:1:0.2; SM : PC: CH : polyethylene glycoi DPPE 1: 1: 1: 0.2 and PC: CH 2: 1 was different (Allen and Hansen, 1991). ~-Adrenergic receptor and subunits of GTPbinding regulatory protein were reconstituted into POPC : PG (2 : 1 w/w) and PE : PS (3 : 2 w/w) vesicles (Rubenstein et al., 1991). Poly (2-methacryloyloxyethyl phosphorylcholine) reduces the adsorption on glass of albumin, IgG, fibrinogen, fibronectin, Hagemson factor (factor XII), factor VIII/van Willebrand factor, high-molecular-weight kininogen, and the complement protein C5 of human plasma (Ishihara ef al., 199Ib). The bolus intravenous infusion factor Xa entrapped in PCjPS liposomes inhibits the bleeding diathesis of haemophilic (factor VIII deficient) dogs (Ni and Giles, 1992). Coagulation factor VIIa binds to PCjPS mixtures, whereas tissue factor,.z,, and TF,_z,9. Factor VIIa complex do not. Factor X is preferentially cleaved by the soluble complex, when associated with the phospholipid surface (Ruf et al., 1991). DMPC and DPPC reduce the transmonolayer resistance of MDCK cells (Jabar and Dawson, 1991). PC: CH : 7-ketoCH (4: 3: 1 by weight) and PC : CH (1: 1 by weight) liposomes considerably reduce the colony-forming ability of Chinese hamster cells (Khokhlov et al., 1991). Bacteriorhodopsin modifies the thermal behavior (phase transition parameters) of large DPPC hposomes by interacting with them (Piknova et al., 199lf. Binding to PC liposomes may decrease the rate of clearance or degradation of the encephahtogenic peptide in guinea pig when given intraperitoneally (Avrilionis and Boggs, 1991). Ovalbumin entrapped in DOPC, PS, CL and dioleoylsn-3-succinyl glycerol liposomes induced cytotoxic T lymphocyte in uiuo (Reddy et al., 1992). Glycophorin modified the bilayer internal pressure of DOPC and DPPC monolayers (Davies and Jones, 1992). New methods have been developed to measure the chloride influx into phospholipid vesicles caused by glycine receptor. The giycine receptor was purified from rat spinal cord (Garcia-Calve et al., 1992). REFERENCES

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Interaction

of phospholipids

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