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Integrin modulating factor-1: a lipid that alters the function of leukocyte integrins
WONITOR Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene R. MEDORI E T A L
N. Engl. J. Med. 326, 444-449
The grim tally of neurological diseases identified as 'prion diseases' is rising. Medori et al. have studied a large Italian kindred afflicted with an autosomal dominant disease involving progressive, untreatable insomnia and impairment of the autonomic, endocrine and motor systems. The disease, which they call fatal familial insomnia (FFI), eventually causes hallucinations and then coma, killing most patients by the age of 50. Prion diseases are associated with mutations in the prion protein (PrP) gene that produce an altered, protease-resistant isoform of PrP. Medori et al. have analysed the PrPs in FFI family members and in patients with the sporadic form of another neurodegenerative prion dis-
Yeast RAD14 and human xeroderma pigmentosum group A DNA-repair genes encode homologous proteins M. BANKMANN, L. PRAKASH AND S. PRAKAStt
N a t u r e 355, 555-558
The fundamental cellular process of DNA repair has, like the cell cycle, turned out to have many similarities in yeast and mammals. Bankmann el al. have cloned the yeast R A D 1 4 gene by complementation of a r a d l 4 mutation, and show that R A D 1 4 is essential for the incision step of the excision repair pathway, which repairs DNA damaged by ultraviolet light. The sequence of the RAD14 protein, a very hydrophilic protein containing a zinc finger motif and another potential metal-binding motif, shows significant homology to the human XPAC protein. The X P A C
Integrin modulating factor-l: a lipid that alters the function of leukocyte integrins A. ItERMANOWSKI-VOSATKA, J.A.G. VAN STRIJP, W.J. SWIGGARD AND S.D. WRIGHT
Cell 68, 341-352 The interaction between two cells depends on the type, number and properties of surface adhesion molecules. While many types of surface receptors are known, evidence is increasing that their adhesive qualities can be modified by other membrane components, suggesting an additional level of control beyond simple up- or downregulation of receptor numbers. Hermanowski-Vosatka et al., for example, have identified a lipid factor
ease, Creutzfeldt-Jakob disease. They show that four affected members of the FFI kindred, and 11 of the 29 unaffected members (some of them over 60 years of age), have altered PrPs associated with a GAC-+AAC point mutation in codon 178 of the PrP gene. Their altered PrPs are different from those found in the Creutzfeldt-Jakob patients. However, the relationship between mutation and disease phenotype is far from straightforward. Not only is it puzzling that several unaffected members of the FFI family carry the codon 178 mutation, but Medori et al. also compare their patients with those in three other kindreds known to have the same codon 178 PrP mutation, and note that the clinical findings vary widely. For example, some kindreds show spongiosis of the cerebral cortex and some d ° not. The genetic or epigenetic factors underlying such variation remain to be identified.
The apical localization of transcribing RNApolymerases on supercoiled DNA prevents their rotation around the template B. TEN HEGGELER-BORDIER E T A L
gene lies in the group A complementation group of the cancer-prone syndrome xeroderma pigmentosum (XP); the underlying defect in XP is believed to be in the incision step of excision repair. Bankmann et al. show that in yeast R A D 1 4 is required only in excision repair, since mutants with complete deletions of r a d l 4 ( r a d l 4 A ) are viable and capable of mitotic intrachromosomal recombination. R A D 1 4 brings to six the number of yeast genes shown to be essential for incision: RAD1, 2, 3, 4, 10 and I4. Further studies on the roles of these genes and interactions between them (for example, Bankmann et aL show that r a d l 4 k and r a d l A are epistatic to one another) are bound to be relevant to the human excision repair pathway as well.
EMBOJ. 11, 667-672 The relative movement of RNA polymerase and its DNA template during transcription has been the subject of controversy. Does the polymerase move around the template or vice versa? Ten Heggeler-Bordier et aL have studied a simple in vitro system consisting of purified E. coli RNA polymerase and a supercoiled plasmid template containing two available promoters. The molecules were visualized by a cryo-electron microscopy method that allows observation of unstained DNA molecules suspended in a vitrified solution. The striking result was that 95% of promoter-bound polymerase molecules were seen at apices of loops in the supercoiled DNA, and remained at apices during transcription. Nascent RNA molecules were not entangled round the DNA, as would be expected if the polymerase were rotating, but appeared as random coils near the polymerase. Ten Heggeler-Bordier et al. favour a model in which binding of the polymerase to a promoter induces bending of the DNA and formation of an apical loop; the polymerase also induces bending during transcription, thus causing the DNA to rotate around its axis and the apical loop to move along the DNA. Although these experiments were done in vitro, they may mirror what happens in vivo, both in prokaryotes and eukaryotes. A major requirement of the model is that the DNA within transcriptional domains must be free to rotate; the implications of this requirement for chromatin structure and dynamics need further investigation. ~'~
that increases the avidity of the type 3 complement receptor (CR3, an OtM[3e integrin) for its ligand, complement fragment C3bi. CR3 is expressed on polymorphonuclear leukocytes (PMNs) but binds weakly to ligand unless the cells are stimulated, when avidity (but not receptor number) is increased. The new factor, integrin-modulating factor-1 (IMF-1), was extracted from phorbol ester-stimulated PMNs, and when added to resting PMNs led to a rapid increase in their binding to C3bi. Similarly, binding of purified CR3 to C3bi was massively increased in the presence of IMF-1. Production of this activity by stimulated cells is transient, as is C3bi binding, suggesting that IMF-1 may control ligand
binding by CR3. IMF-1 affects the binding of other CR3 ligands (e.g. fibrinogen), and also stimulates binding by the lymphocyte adhesion protein LFA-1, which binds ICAM-1 on nearby cells and hence catalyses homotypic aggregation. Despite a barrage of biochemical tests, the exact nature of IMF-1 is unclear, although numerous possibilities have been ruled out. The best bet is that it is a 340 Da unsaturated fatty acid which, on stimulation, allosterically activates the integrins CR3 and LFA-1. Cell recognition processes are also important outside the irmnune system, especially in development, and it will be inter esting to see if similar mechanisms recur elsewhere. J-~
TIG APRIL1992 VOL. 8 NO. 4
i23
N. Engl. J. Med. 326, 444-449
The grim tally of neurological diseases identified as 'prion diseases' is rising. Medori et al. have studied a large Italian kindred afflicted with an autosomal dominant disease involving progressive, untreatable insomnia and impairment of the autonomic, endocrine and motor systems. The disease, which they call fatal familial insomnia (FFI), eventually causes hallucinations and then coma, killing most patients by the age of 50. Prion diseases are associated with mutations in the prion protein (PrP) gene that produce an altered, protease-resistant isoform of PrP. Medori et al. have analysed the PrPs in FFI family members and in patients with the sporadic form of another neurodegenerative prion dis-
Yeast RAD14 and human xeroderma pigmentosum group A DNA-repair genes encode homologous proteins M. BANKMANN, L. PRAKASH AND S. PRAKAStt
N a t u r e 355, 555-558
The fundamental cellular process of DNA repair has, like the cell cycle, turned out to have many similarities in yeast and mammals. Bankmann el al. have cloned the yeast R A D 1 4 gene by complementation of a r a d l 4 mutation, and show that R A D 1 4 is essential for the incision step of the excision repair pathway, which repairs DNA damaged by ultraviolet light. The sequence of the RAD14 protein, a very hydrophilic protein containing a zinc finger motif and another potential metal-binding motif, shows significant homology to the human XPAC protein. The X P A C
Integrin modulating factor-l: a lipid that alters the function of leukocyte integrins A. ItERMANOWSKI-VOSATKA, J.A.G. VAN STRIJP, W.J. SWIGGARD AND S.D. WRIGHT
Cell 68, 341-352 The interaction between two cells depends on the type, number and properties of surface adhesion molecules. While many types of surface receptors are known, evidence is increasing that their adhesive qualities can be modified by other membrane components, suggesting an additional level of control beyond simple up- or downregulation of receptor numbers. Hermanowski-Vosatka et al., for example, have identified a lipid factor
ease, Creutzfeldt-Jakob disease. They show that four affected members of the FFI kindred, and 11 of the 29 unaffected members (some of them over 60 years of age), have altered PrPs associated with a GAC-+AAC point mutation in codon 178 of the PrP gene. Their altered PrPs are different from those found in the Creutzfeldt-Jakob patients. However, the relationship between mutation and disease phenotype is far from straightforward. Not only is it puzzling that several unaffected members of the FFI family carry the codon 178 mutation, but Medori et al. also compare their patients with those in three other kindreds known to have the same codon 178 PrP mutation, and note that the clinical findings vary widely. For example, some kindreds show spongiosis of the cerebral cortex and some d ° not. The genetic or epigenetic factors underlying such variation remain to be identified.
The apical localization of transcribing RNApolymerases on supercoiled DNA prevents their rotation around the template B. TEN HEGGELER-BORDIER E T A L
gene lies in the group A complementation group of the cancer-prone syndrome xeroderma pigmentosum (XP); the underlying defect in XP is believed to be in the incision step of excision repair. Bankmann et al. show that in yeast R A D 1 4 is required only in excision repair, since mutants with complete deletions of r a d l 4 ( r a d l 4 A ) are viable and capable of mitotic intrachromosomal recombination. R A D 1 4 brings to six the number of yeast genes shown to be essential for incision: RAD1, 2, 3, 4, 10 and I4. Further studies on the roles of these genes and interactions between them (for example, Bankmann et aL show that r a d l 4 k and r a d l A are epistatic to one another) are bound to be relevant to the human excision repair pathway as well.
EMBOJ. 11, 667-672 The relative movement of RNA polymerase and its DNA template during transcription has been the subject of controversy. Does the polymerase move around the template or vice versa? Ten Heggeler-Bordier et aL have studied a simple in vitro system consisting of purified E. coli RNA polymerase and a supercoiled plasmid template containing two available promoters. The molecules were visualized by a cryo-electron microscopy method that allows observation of unstained DNA molecules suspended in a vitrified solution. The striking result was that 95% of promoter-bound polymerase molecules were seen at apices of loops in the supercoiled DNA, and remained at apices during transcription. Nascent RNA molecules were not entangled round the DNA, as would be expected if the polymerase were rotating, but appeared as random coils near the polymerase. Ten Heggeler-Bordier et al. favour a model in which binding of the polymerase to a promoter induces bending of the DNA and formation of an apical loop; the polymerase also induces bending during transcription, thus causing the DNA to rotate around its axis and the apical loop to move along the DNA. Although these experiments were done in vitro, they may mirror what happens in vivo, both in prokaryotes and eukaryotes. A major requirement of the model is that the DNA within transcriptional domains must be free to rotate; the implications of this requirement for chromatin structure and dynamics need further investigation. ~'~
that increases the avidity of the type 3 complement receptor (CR3, an OtM[3e integrin) for its ligand, complement fragment C3bi. CR3 is expressed on polymorphonuclear leukocytes (PMNs) but binds weakly to ligand unless the cells are stimulated, when avidity (but not receptor number) is increased. The new factor, integrin-modulating factor-1 (IMF-1), was extracted from phorbol ester-stimulated PMNs, and when added to resting PMNs led to a rapid increase in their binding to C3bi. Similarly, binding of purified CR3 to C3bi was massively increased in the presence of IMF-1. Production of this activity by stimulated cells is transient, as is C3bi binding, suggesting that IMF-1 may control ligand
binding by CR3. IMF-1 affects the binding of other CR3 ligands (e.g. fibrinogen), and also stimulates binding by the lymphocyte adhesion protein LFA-1, which binds ICAM-1 on nearby cells and hence catalyses homotypic aggregation. Despite a barrage of biochemical tests, the exact nature of IMF-1 is unclear, although numerous possibilities have been ruled out. The best bet is that it is a 340 Da unsaturated fatty acid which, on stimulation, allosterically activates the integrins CR3 and LFA-1. Cell recognition processes are also important outside the irmnune system, especially in development, and it will be inter esting to see if similar mechanisms recur elsewhere. J-~
TIG APRIL1992 VOL. 8 NO. 4
i23