Ca2+-dependent carbohydrate-recognition domains in animal proteins

Ca*+-dependent

carbohydrate-recognition in animal proteins

domains

Kurt Drickamer Columbia

University, New York, USA

(C-type) animal lectins contain a common Ca2+-dependent sequence motif, with 14 invariant and 18 highly conserved residues distributed over discrete carbohydrate-recognition domains of 115-130 amino acids. Domains that display the C-type carbohydrate-recognition domain motif are found in an increasing number of proteins, although only some are known to bind carbohydrate. Progress is being made towards making deductions about the structure and activity of these domains from their sequences.

Many

Current

Opinion

in Structural

Introduction

@+-dependent carbohydrate-recognition domains (Ctype CRDs) were initially identified in the mammalian asialoglycoprotein receptor, its chicken homolog, and serum mannose-binding proteins [ 11. Sequence alignments have led to the identification of more than 50 additional proteins that contain domains related to these CDs. Comparison of these sequences reveals the presence of a common sequencemotif consisting of 14 invariant and 18 highly conserved residues (Fig. 1). The CRDs are found associatedwith various domains that have been identified in other extracellular and cell-surface proteins 121.C-type animal lectins can be classified into groups which are based either on the overall architecture of the protein and the position of the CRD relative to other domains (Fig. 2) or the degree to which the sequencesof their CRDs are related (Fig. 3). In general, the groups defined by these two approaches are the same. Recent additions to the collection of C-type CRDs will be discussed in the first two sections of this review. These are followed by a summary of progress made -s--

Biology

1993, 3:393-400

in understanding the evolutionary, structural, and functional significance of the sequence similarities observed in this family of protein domains. The biological roles of diverse C-type lectins have been discussed in detail elsewere [3]. Structurally distinct groups of lectins, such as the soluble, P-galactoside-binding(S-type) lectins and the mannose 6-phosphate receptors (P-type lectins), have been considered in other recent reviews [4,5].

Variations

on established

-

themes

New examples of C-type CRDsin proteins that are similar to known lectins have been reported during the past year. In addition to the human E-, L- and P-selectins,murine homologs of all three proteins have now been cloned [ 6,7], as have rabbit E-selectin [ 81 and rat L-selectin [ 91. But, in any one species, at most onlv three of these celladhesion molecules have been described. It remains to be seen whether the selectin-like protein that mediates endothelial-cell capillary formation is a bovine form of E-

n ----------;-~--e---C------e--e-O--E--~--

s---s------s

Fig. 1. Sequence motif in C-type CRDs. Invariant residues are indicated in ‘the one letter amino acid code. Residues that are conserved in character are designated: @, aromatic; 8, aliphatic; R, either aromatic or aliphatic; and 0, oxygen-containing. A version of this motif has been entered in the PROSITE database as the C-type lectin domain signature KTD.

~--------0-n--G--n------n--u---

I

ZP-----------EOCe-n--------G-uND--C------n-C-

CRD-carbohydrate-recognition @ Current

Abbreviations domain; ECFLepidermal Biology

Ltd ISSN 0950440X

growth

factor.

393

394

Sequences aid topology

GROUP II (GROUP VI

-

GROUP IV

GROUP VI

GROUP Ill

GROUP I

Fig. 2. Summary of the structures of several groups of C-type animal lectins. Representative structures for four groups of membrane-associated lectins are shown. Groups II and V are represented by the chicken hepatic lectin, the homolog of the mammalian asialoglycoprotein receptor. Group IV consists of the selectin cell-adhesion molecules, such as L-selectin. The macrophage mannose receptor is the only lectin in group VI. Three groups of water-soluble lectins are also depicted: group Ill lectins (collectins), such as mannosebinding protein, are found in extracellular fluids; group I CRD-containing proteins are proteoglycans of the extracellular matrix; and group VII consists of CRDs without flanking domains. Other domains shown: ECF, ECF-like domains; CR, complement-regulatory repeats; FN-II, fibronectin type II repeats; COL, collagen-like sequences; GAG, glycosaminoglycan attachment sites; and HA, link protein homology domains. C, carboxyl terminus; N, amino terminus.

NNN

NNN

c

GROUP VII

or P-selectin,or representsa new member of the selectin group (M Nguyen,NA Strubel,J Bischoff, abstract,J Cell Biochem 1992, Sl6Dl75).

The term collectin is now being used to describe the group III C-type lectins, denoting the presence of both collagenousand &in-like segmentsin a single polypeptide. Severaladditional collectin sequenceshave recently been reported, including murine homologs of the two forms of rat mannose-binding proteins [lo], and murine and human forms of a minor pulmonary surfactant protein, SP-D [il-131. These proteins continue to cluster into two subgroups distinguishable by the size of their collagenous segments.The presence of longer collagenous domains is correlated with the formation of large,cruciform aggregatesfrom trirneric building blocks, whereas the shorter collagen tails generally lead to the association of trimers into bouquet-like structures [ 141. Proteins in both subgroups are believed to mediate an innate immune response to pathogens. One of the most diverse groups of C-typeanimal lectins is the category of type II transmembrane receptors, which mediate glycoprotein endocytosis and degradation. The group II lectins consist of carboxy-terminal CRDslinked to amino-terminal, Internal signal/membrane anchor sequences.As noted above, proteins of this type, including the hepatic asialoglycoprotein receptor, were among the first C-type lectins to be described. A close homolog of this protein isolated from mouse tumoricidal macrophages has recently been cloned [ 151. A more divergent member of group II is a mannose-specificreceptor isolated from human placenta [16=*].

The carboxy-terminal domain structures of extracellular matrix proteoglycan core proteins (group I> are proving to be unexpectedly diverse. Variant splicing forms of the mRNiU for aggrecan, the aggregating proteoglycan of cartilage, have been described, in which the epidermal growth factor (EGF)-like domains or the complementbinding repeats, usually found on either side of the C-type CRD, are deleted [ 171. A novel brain proteogly can, neurocan, has also been isolated and cloned [ 1WI. Like versican, a core protein from fibroblasts, neurocan contains two repeatsof the EGF-like domain.

New structural

categories

Several recently determined sequences have resulted in the definition of two new groups of C-type animal lectins. The existence of proteins that appear to be free CRDs, not appended to any other polypeptide segment, has been known for some time. But until recently, most of these proteins had been isolated from invertebrate sourcesand characterizedat the protein level. Becauseof their evolutionary distance from the vertebrate proteins, it is diicult to relate their sequencesto the other C-type lectins. In addition, until cDNA sequencesfor these proteins have been established, it is impossible to be sure that they are not fragments derived from larger precursors by proteolytic processing. Severalvertebrate cDNAS encoding free-standing CRDs have recently been described. The sequences of sev-

Ca*+dependent

carbohydrate-recognition

domains

Drickamer

Gal LEC TYPE II RECEPTORS

FREE CROs

”

VII

IHuI MANNOSE RECEPTOR

SELECTINS

1601

1

COLLECTINS .

CONGLUT~N~N

r

1

I”

11,

IHub TETRANECTIN IHUI EOSONOPHIL GRANULE PROTEIN IHW NKGZA IHul

NKGZC

lHul

NKGZO

IRal

NK-PI

IMol NK-PI-2 WI

NK-Pl-34

.

_

NK

IMol NK-PI.40 IMOI LY49B IMOI LY49C IMol LY49A IMol ANTIGEN --GENE DUPLICATION

--SPECIES DIVERGENCE

. (Tj 9 _

TYPE II LYf&yzfNyE

V

Fig. 3. Dendrogram summarizing sequence similarity between various Ctype CRDs. Similarities were determined on the basis of comparison of amino acid sequences of the CR0 portion of each protein, using a cluster analysis program 1571. The computer-generated tree has been modified for clarity by the segregation of the CRDs of the mannose receptor from the other proteins. At the bottom are shown the approximate regions of the dendrogram corresponding to either the divergence of protein sequences following duplication of genes to serve new functions or the divergence of proteins with homologous functions in-different species. The division between these two regions is not precise, because different proteins diverge at distinct rates. The fact that the C-type animal lectins fall into the same categories in this figure and the preceding one indicates that the shuffling of exons to form a precursor with a, given protein architecture occurred only once during evolution. Thus, all proteins with similar domain organization are descended from a common ancestor. References for sequences may be found in I411 and in the text. Sequences of lectins from lower vertebrates and invertebrates are not included. 60, cow; Ch, chicken; Do, dog; HEP, hepatocyte; Hu, human; LEC, lectin; MO, mouse; Ma, macrophage; Ra, rat; Rb, rabbit.

395

3%

Sequences aid topology

et-al of these CRDs place them in a cluster (group VII in Fig. 3). Because these proteins have been isolated from several.diEerent species, it is not easy to be certain which are homologs of each other. The sequence comparispns suggest the probable existence of at least two distinct mammalian group VII proteins, one represented by the pancreatic stone protein [ 19,201,and the other represented by the pancreatic thread protein [2l], pancreatitus-associatedprotein 1221,and a newly described hepatoma-associatedprotein (which is Iso expressed in pancreas) [23**]. Tetranectin, a human serum protein which binds to the fourth kringle domain of plasminogen,is not included in this group becauseits sequenceis quite divergent from the other CRDsin this group, and becauseit is not known whether this polypeptide is produced by degradation of a larger precursor [24]. The major basic protein of human eosinophil granules, which has been independently isolated as an immunoregulatory factor [ 251, likewise does not cluster with any of the known groups. Proteins from lower vertebrates related to some of the mammalian and avian proteins shown in Figs 2 and 3 have been described. Two snake venom proteins, a galactose-binding lectin [26] and a coagulation factor IX/X-binding protein [27] are isolated C-type CRDsthat cluster with the group VII CRDs.Two fonns of phospholipase A2 inhibitor [28] are also free CRDsand are very closely relatedin sequenceto eachother, but do not cluster with any of the groups in Fig. 3. Finally, two antifreeze proteins from fish serum [ 29*,30*] are distantly related to the group I and II lectins in mammalsand birds. An increasing number of cDNAs encoding type II transmembrane proteins, similar in overall structure to the group II C-type animal lectins, have been isolated from natural killer lymphocyte libraries [31-351. Similar proteins have also been identified on the surface of T and B cells [36-381. The putative CRDs in these group V proteins are highly divergent from the other sequences compared in Fig. 3. Some are also highly divergent from each other. The possible functions of these proteins are discussedbelow.

Cenomic

organization

The intron-exon organization of severalgenes encoding C-type CRDshas been described. In each case,the CRDencoding region js separatedfrom the remainder of the gene by an intron. In addition, the coding sequencesfor CRDsark interrupted by two introns in group I and II proteins [39=-l, and three introns in group VII proteins [19]. The positions of these introns are identical within each group, but are shifted between any two groups [40]. The CRDs in other groups are encoded entirely on uninterrupted exons. Thus, the genomic organization reflectsthe samecategorization as the sequencecomparisons and overall protein architecture. The gene for the macrophagemannose receptor is the most complex yet examined, consisting of 30 exons [41]. The pattern of introns within its CRDsdoes not correlate with the inter-

ruptions seen in the other groups of CRDS,reflecting the early divergence of this receptor.

Structure-evolution

correlations

The determination of the three-dimensional structure of the CRD from rat serum mannose-binding protein provides a basis for understanding the role of the residues that make up the C-type CRD motif [42,43**]. Residues that define the motif establish the overall fold of the CRD (Fig. 4) by creating: two conserved disulfide bonds; binding sites for two bound Cal+; several turns; and an extended hydrophobic core. Hence, it can be concluded that the motif residues have been conserved in order to maintain the basic fold of the domain. Therefore, all of the domains that share this set of conserved residueswill probably be folded in similar ways. Severalancillary pieces of evidence are consistent with the idea that the folds of proteins possessing the Ctype CRD motif are similar. Wherever the topology of disullide-bond formation has been established, it is the same as in the mannose-binding CRD. In addition, circular-dichroism spectroscopy suggeststhat the CRDs that have been examined contain levels of o!and p structure similar to that observed in the crystal structure of the mannose-binding CRD(K Drickamer, unpublished data). Finally, all of the domains that have been examined display Ca’+ -dependent activity. Yet the number of Ca’+ binding sites is not always known. For instance, many of the ligands that form the Ca2+-binding site 1 in the mannose-binding CRD are absent from the selectins. In spite of this difference, there is evidence for two divalent cation-binding sites in P-selectin [44]. Studies identifying severalCa2+-binding peptide mimics of subdomains of P-selectin are difficult to interpret, because these do not correspond to either of the Ca2+-binding sites observed in the mannose-binding CRD [45]. An important aspect of the CRD structure is that the amino-terminal and carboxy-terminal ends are located close to each other. This arrangementcontrastswith that in some other extracellular protein modules, such as immunoglobulinlike domains, which have a ‘pass through’ topology. This type of topological consideration clearly affects the way in which domains can be shuffled and juxtaposed.

Sugar-binding

activity

and specificity

Crystallography

It is one thing to use a sequence motif, such as the one identified with the C-type CRDs,to predict that domains are folded in similar ways, and another to predict the activity of such a domain. An important guide in this respect’is the recently described structure ‘of the mannosebinding protein complexed with a mannose-containing oligosaccharide [43**]. The structure reveals that the equatorial 3- and 4-hydroxyl groups of mannose are coordinated to one of the bound Ca*+ ions (Ca2+ 2 in Fig.

Ca*+-dependent

4), and that four of the protein side chains that are also coordinated to this Ca*+ (two asparagine and two glutamic acid residues) are hydrogen bonded to these same sugar hydroxyl groups (Fig. 4). The remaining ligands for Ca*+ 2 are contributed by the side chain of an aspartic acid residue. The presence of these five amino acid side chains becomes an important criterion for predicting that a CRDlike domain. will have the capacity to bind sugars in a manner analogous to the mannose-binding CRD. Indeed, these five residues are completely conserved in CRDsthat bind mannose,glucose, and other sugars with equatorial 3- and 4hydroxyl groups. It is also striking that in CRDs known to bind galactose preferentially, two of the liganding residues are different. One asparagine position in the mannose-binding CRD is always occupied by aspartic acid in galactose-binding CRDs, and one of the glutamic acids is replaced by glutamine. Modification of the mannose-binding CRD by incorporation of these two changes results in a change to preferential binding of galactose [46]. The sugar-binding site is not related to that predicted from sequence comparisons with other sugar-binding proteins [47].

Mutagenesis

As expected from the crystallographic results, extensive mutagenesisof the CRD from rat serum mannose-binding protein reveals that residues over much of the sur-

(a)

l

carbohydrate-recognition

domains

Drickamer 397

face of the domain can be changed without altering sugar-binding activity, whereas changes in the conserved Ca*+ ligands usually lead to loss of binding activity [48]. More surprising is the finding that changes in many of the conserved residues that make up the hydrophobic core of the domain result in loss of sugar-binding activity as an indirect result of decreased affinity for Ca*+. This decreased affinity must result from subtle changes in the arrangement of the loops that form the Caz+binding sites (Fig. 4). The phenotype of these mutants might mimic the changes brought about at low pH, such as in endosomes,when C-type CRDsreleasetheir ligands. A second important source of information about sugar binding has been tile mutagensis of E-selectin [49**]. These studies point to the importance of a second region of the CRD,which includes two lysine residues that are needed for binding to the sialyl Lewis x epitope, a natural ligand for this protein [50]. The residues at Ca*+ 2 in the selectins are the same as those in the mannosebinding CRD. As fucose binds to the mannose-binding protein, probably through the 2- and 3-hydroxyl groups, it is possible that the fucose portion of the sialyl Lewis x tetrasaccharide binds to selectins in a similar way. The _ critical sialic acid terminal residue might then bind at the second site identified in the mutagenesis studies. Some ligands may bind to this second site in a Ca’+ independent manner [51]. It will be interesting to see whether the sequence in this region can be correlated with saccharide-binding specificit$ in other CRDs.

(b)

ASP 2lK

Fig. 4. Structureof C-type CRD from rat serum mannose-binding protein complexed with mannose-containing oligosaccharide. (a) Ribbon diagram showing secondary structure elements of the mannose-binding CRD complexed with a glycopeptide from ovalbumin containing six mannose residues. Spheres l-3 represent Caz+ Ions observed in the crystal structure. Only the first two are believed to be present in the soluble CRD. (b) Detailed view of region surrounding Ca2+ 2. The Ca2+ Ion is shown as a light grey sphere. White, dark grey, and black spheres represent carbon, nitrogen and oxygen, respectively. Ca2+- coordination bonds are denoted by long thick dashes, whereas short dashes represent hydrogen bonds. Numbers on the mannose carbon atoms represent ring positions. The cl-glycosidic bond to the next sugar of the oligosaccharide (at carbon 1) has been cut off for clarity. Published with permission [4X**].

398

Sequences’

and topology

Predictions

5.

KORNFEUI

On the basisof’these findings, it is possible to make more informed interpretations of sequencescontaining the C-

6.

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7.

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8.

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9.

WATMABE

10.

SA~TXY K, Z\HEDI K, LI~IJAS J-M, WHITI:.HEA~ AS, Eze~ow?r~ RAB: Molecular Characterization of the Mouse MannoseBinding Proteins: the Mannose-Binding Protein A but not C Is ?n Acute Phase Reactant. J fn7r77rr~rol 1991, 147:692-697.

11.

RLIS~‘ K. GROSSO L, ZHANG V, CHANG D, PIX~SON A, LONGUORE W, CAI G-Z. CROLICH E: Human Surfactant Protein D: SP-D Contains a C-Type Lectin Carbohydrate Recognition DoBiop/+ 1991, 290:116-126. main. &cl) /3ioc/~c~~t

12.

SHI~IIZU H. FISHEH JIH. PAPS?’ P. BENSON B, late K. SEASON RJ, \rOELKeK DR: Primzuy Structure of Rat Pulmonary Surfactant Protein D: cDNA and Deduced Amino Acid Sequence../ Hiol Gr,cm 1992, 26731853-1857.

13.

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type CRD motif, as CRDs containing the five Ca’+ 2 ligands iri either the mannose- or galactose-binding configuration would be better candidates for carbohydrate-binding activity than CRDs that do not. An interesting test case is the lymphocyte low-affinity receptor for the Fc portion of IgE (CD23). The &E-binding domain of this group II protein has been shown to correspond to the segment most similar to bona fide 0s [52-l. The mouse form of this protein contains all of the residues expected of a mannose-binding CRD, whereas one of the asparagine residues is replaced by threonine in the human version. Evidence for the involvement of carbohydrates in the CD23-IgE interaction is conflicting. A peptide from IgE is able to inhibit the interaction, indicating that protein forms at least part of the binding determinant [53]. Although sugars do not compete effectively [54], experiments employing tunicamycin to prevent glycosylation suggest that sugars are required for the interaction of CD23 with a novel ligand, CD21 [ 550,56*]. One pos-

sibility is that, like the selectins, ~~23 may have a dual interaction, in this case with both protein and carbohydrate. One of the most interesting cases for considering possible ligand-binding activity is the group V family of natural killer cell-surface proteins. As noted above, this family is quite diverse in sequence. Many of the members are lacking one or more of the Ca’+ 2 ligands, making it unclear whether or not these proteins bind Cal+, much less saccharide ligands.

References

and recommended

Papersof particularinterest,published

reading within

the annual

period

of

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2.

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D.

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IS.

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16. ..

Cl1RTlS

BM, SCHARvOW%E

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and

Exthat of Human Immunodefigpl20. I-‘rw N&l Acd

pression of a Membrane-Associated C-Type Lectin

Exhibits CD4-lndependent Binding ciency Virus Envelope Glycoprotein Sci USA 1992, 89:83%-8360. A novel mannose-binding receptor, cloned from placenta on rhe basis of its ability to confer HIV-sensirivky on cells, is closely related in sequence to other group II receptors but has a unique carbohydmtebinding specilicky. 17.

review, have been hiRhlinhred 35: . of special interest .. of outstanding interest 1.

of the Mannose 6. II Receptors. A77t7rt

1-l.

Acknowledgements I thank Maureen Tzzyior for comments on the manuscript. K Drickamer is a recipientof a l%cult) SakiryAmrd from the American Cancer Society.

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Anr7u

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L%%ERRE C, CHIUSTA L, SI~ION M-T, VERNIEH P, BRECHOT C: A Novel Gene (HIP) Activated in Human Priiary Liver Cancer. tinter Res 1992, 52:5089-5095. In addition to describing a new CRDcontaining protein found in hep atomas, this paper clarifies the relationship between other group VU proteins, suggesting that the pancreatic stone protein and the pancreatic thread protein are distinct.

33.

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*

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42.

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27.

28.

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44.

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Sequences and topology tide strong evidence the mannose-binding

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K Drickamer, Department of Biochemistry and Molecular Biophysics, Columbia University, 630 West 168th Street, New York, New York 10032, USA.