Ligand Binding to Integrins

Abstract

ligand competent metal ion-dependent adhesion site monoclonal antibody intracellular adhesion molecule vascular cell adhesion molecule mucosal addressin cell adhesion molecule The “integrin” terminology was applied in a 1987 review article (1.Hynes R.O. Cell. 1987; 48: 549-550Abstract Full Text PDF PubMed Scopus (3579) Google Scholar) to describe a family of structurally, immunochemically, and functionally related cell-surface heterodimeric receptors, which integrated the extracellular matrix with the intracellular cytoskeleton to mediate cell migration and adhesion. The three original β subunits (β1, β2, and β3) identified have now expanded to eight, and the number of α subunits stands at 17. These subunits interact noncovalently in a restricted manner to form more than 20 family members. The diversity of integrins is expanded further by alternative splicing, post-translational modifications, and interactions with other cell-surface and intracellular molecules (2.Green L.J. Mould A.P. Humphries M.J. Int. J. Biochem. Cell Biol. 1998; 30: 179-184Crossref PubMed Scopus (48) Google Scholar, 3.Porter J.C. Hogg N. Trends Cell Biol. 1998; 8: 390-396Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar, 4.De Melker A.A. Sonnenberg A. Bioessays. 1999; 21: 499-509Crossref PubMed Scopus (109) Google Scholar). The number of integrins and the remarkable breadth of their cellular distribution support the statement that the phenotype of virtually every cell is uniquely influenced by its display of integrins. Over the past 13 years, more than 14,000 scientific articles have dealt with various aspects of integrin biology and almost 1,000 have appeared in theJournal of Biological Chemistry. This article examines a central aspect of integrin biology: ligand recognition and the structural basis for this function. A hallmark of the integrins is the ability of individual family members to recognize multiple ligands. Indeed, the extent of the integrin family pales in comparison with the number of their ligands. Table Isummarizes the major extracellular ligands of integrins; the listing is undoubtedly incomplete. The list includes a large number of extracellular matrix proteins (bone matrix proteins, collagens, fibronectins, fibrinogen, laminins, thrombospondins, vitronectin, and von Willebrand factor), reflecting the primary function of integrins in cell adhesion to extracellular matrices. Many “counter-receptors” are ligands, reflecting the role of integrins in mediating cell-cell interactions. Included are numerous microorganisms, which utilize integrins to gain entry into cells. There are direct and multiple linkages between integrins and host defense systems, created by their recognition of hemostatic and complement factors. The preference of any given integrin among its ligands is determined by relative affinity, availability within a specific microenvironment, and the conformational state of the ligand, which controls exposure of its integrin recognition sequence.Table IIntegrin extracellular ligandsLigandIntegrinAdenovirus penton base proteinαvβ3, αvβ5Bone sialoproteinαvβ3, αvβ5Borrelia burgdorferiαIIbβ3Candida albicansαMβ2Collagensα1β1, α2β1, α11β1, αIbβ3Denatured collagenα5β1, αvβ3, αIIbβ3Cytotactin/tenascin-Cα8β1, α9β1, αvβ3, αvβ6DecorsinαIIbβ3Disintegrinsαvβ3, αIIbβ3E cadherinαEβ7Echovirus 1α2β1Epiligrinα3β1Factor XαMβ2Fibronectinα2β1, α3β1, α4β1, α4β7, α5β1, α8β1, αvβ1, αvβ3, αvβ5, αvβ6, αvβ8, αIIbβ3Fibrinogenα5β1, αMβ2, αvβ3, αxβ2, αIIbβ3HIV Tat proteinαvβ3, αvβ5iC3bαMβ2, αxβ2ICAM-1αLβ2, αMβ2ICAM-2,3,4,5αLβ2Invasinα3β1, α4β1, α5β1, α6β1Lamininα1β1, α2β1, α6β1, α7β1, α6β4, αvβ3MAdCAM-1α4β7Matrix metalloproteinase-2αvβ3Neutrophil inhibitory factorαMβ2Osteopontinαvβ3PlasminogenαIIbβ3Prothrombinαvβ3, αIIbβ3Sperm fertilinα6β1Thrombospondinα3β1, αvβ3, αIIbβ3VCAM-1α4β1, α4β7Vitronectinαvβ1, αvβ3, αvβ5, αIIbβ3von Willebrand factorαvβ3, αIIbβ3 Open table in a new tab A primary goal of many structure-function analyses in the integrin field has been the reduction of macromolecular ligands to minimal recognition sequences. This endeavor has been highly successful, and many bioactive amino acid sequences have been teased out of large extracellular matrix proteins (5.Ruoslahti E. Annu. Rev. Cell Biol. 1996; 12: 697-715Crossref Scopus (2633) Google Scholar). The prototypic example is the RGD sequence. RGD was originally identified as the sequence in fibronectin that engages the fibronectin receptor, integrin α5β1, but now is known to serve as a recognition motif in multiple ligands for several different integrins (see Table II). Although RGD peptides inhibit ligand binding to integrins with an RGD recognition specificity (Table II), these receptors can discriminate among RGD-containing ligands. The context of the RGD sequence (flanking residues, three-dimensional presentation, and individual features of the integrin binding pockets) determine whether productive interactions occur (6.Haas T.A. Plow E.F. Curr. Opin. Ce