A discrete site modulates activation of I domains. Application to integrin alphaMbeta2.
A central characteristic of integrin adhesion receptors is their capacity to become activated, thereby enhancing their affinity for ligands. Here, we report the identification of a discrete site within the I domain of integrin alphaMbeta2, which modulates the adhesive activity of this receptor. Based upon the crystal structure, this region is composed of two short and spatially proximal loops, E162QLKKSKTL and Q190NNPNPRS. Mutations in these loops yield receptors which support spontaneous cell adhesion to fibrinogen, whereas mutation of an adjacent region and wild-type receptors require activation to adhere to this substrate. An activating monoclonal antibody enhanced the adhesive activity of one but not the other loop mutants, suggesting that the activation states of these two mutant receptors were not identical. Given that similar I domains exist in several other integrin alpha subunits and non-integrin proteins, and possibly in all integrin beta subunits, these two loop segments may represent a universal target for controlling integrin activation and the function of other I domain-containing proteins. In support of this hypothesis, several naturally occurring mutations that activate von Willebrand factor map to the same loops of its I(A) domain.
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Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Molecular Cardiology, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. ZHANGL@CESMTP.CCF.ORG
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D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology; D002448:Cell Adhesion; D002460:Cell Line; D003179:Complement C3b / Q000378:metabolism; D018604:Epitope Mapping; D005340:Fibrinogen / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D015801:Helminth Proteins / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010047:Ovalbumin / Q000378:metabolism; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid; D014841:von Willebrand Factor / Q000235:genetics / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D006023:Glycoproteins; D015801:Helminth Proteins; D016023:Integrins; D008565:Membrane Proteins; D014841:von Willebrand Factor; C086581:NIF protein, Ancylostoma caninum; D003179:Complement C3b; D005340:Fibrinogen; D010047:Ovalbumin