Unusually stable and long-lived ligand-induced conformations of integrins

Integrins are a large family of cell surface receptors that are involved in a wide range of biological processes. The integrin alpha (IIb)beta (3) (gl ycoprotein IIb-IIIa) is a major platelet glycoprotein heterodimeric recepto r that mediates platelet aggregation and is currently a target for pharmace utical intervention. Ligand binding to the receptor has been shown to induc e conformational changes by physical methods and the exposure of neoepitope s (the ligand-induced binding sites). Here we show that the antagonist XP28 0 induces a conformation that is stable to treatment with SDS and that the protein retains this conformation for several days even after dissociation of the inhibitor. These ligand-induced conformational changes take place wi th purified protein and on intact platelets. They are competable with an RG DS peptide and are stable to reduction but not boiling or treatment with ED TA. The retention of an altered conformation in the absence of the ligand i mplies the possibility of ligand-induced alteration of biological function even in the absence of ligand, Finally, similar behavior is observed with t he integrin alpha (v)beta (3), suggesting that access to SDS stable conform ations may be conserved throughout the integrin superfamily. The unusual st ability, long-lived nature, and potential generality of these conformations could have profound implications for integrin biology.