Homology modelling of integrin EF-hands. Evidence for widespread use of a conserved cation-binding site.
Integrin alpha-subunits contain three or four peptide sequences that are similar to the EF-hand, a 13-residue bivalent cation-binding motif found in calmodulin and parvalbumin. The integrin sequences differ from classical EF-hands in that they lack a co-ordinating residue at position 12. One hypothesis to explain integrin-ligand binding is that aspartate-containing recognition sequences in integrin ligands, which bind at or near to the EF-hand-like sequences, may take the place of the missing residue and co-ordinate directly to the bound cation. In this report, homology modelling of integrin EF-hand-like sequences has been performed using the X-ray structure of calmodulin as a template in order to assess the functional activity of the integrin sequences. In the calmodulin-integrin hybrid structures, integrin EF-hand-like sequences were able to retain cations whereas control sequences did not. Structural analyses demonstrated that the integrin sequences in the hybrid proteins closely resembled conventional EF-hands. The integrin sequences are therefore highly likely to bind Ca2+ ions in vivo, a prerequisite for the ligand-binding model. Database searching with a matrix derived from known integrin EF-hand-like sequences has been used to identify other proteins containing the integrin EF-hand-like motif. Annexin V (anchorin CII), atrial natriuretic peptide receptors and the 70 kDa heat-shock protein were identified by the matrix; the functions of these proteins are known from previous studies to be bivalent cation-dependent. These findings suggest that the integrin EF-hand-like sequence may be a more common motif than originally thought.
Tuckwell
D S
DS
Department of Biochemistry and Molecular Biology, University of Manchester, U.K.
Brass
A
A
Humphries
M J
MJ
D000595:Amino Acid Sequence; D000818:Animals; D017304:Annexin A5; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002147:Calmodulin / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002412:Cations; D005690:Galactose / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009004:Monosaccharide Transport Proteins; D010320:Parvalbumins / Q000235:genetics / Q000378:metabolism; D033902:Periplasmic Binding Proteins; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism; D017461:Receptors, Atrial Natriuretic Factor; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism
D017304:Annexin A5; D002135:Calcium-Binding Proteins; D002147:Calmodulin; D002352:Carrier Proteins; D002412:Cations; D006360:Heat-Shock Proteins; D016023:Integrins; D008565:Membrane Proteins; D009004:Monosaccharide Transport Proteins; D010320:Parvalbumins; D033902:Periplasmic Binding Proteins; D011257:Pregnancy Proteins; D011956:Receptors, Cell Surface; C023550:galactose-binding protein; D009320:Atrial Natriuretic Factor; D017461:Receptors, Atrial Natriuretic Factor; D002118:Calcium; D005690:Galactose