Abstract
The structural basis of the interaction of integrin heterodimers with their physiological ligands is poorly understood. We have used solution x-ray scattering to visualize the head region of integrin alpha 5 beta 1 in an inactive (Ca2+-occupied) state, and in complex with a fragment of fibronectin containing the RGD and synergy recognition sequences. Shape reconstructions of the data have been interpreted in terms of appropriate molecular models. The scattering data suggest that the head region undergoes no gross conformational changes upon ligand binding but do lend support to a proposed outward movement of the hybrid domain in the beta subunit. Fibronectin is observed to bind across the top of the head region, which contains an alpha subunit beta-propeller and a beta subunit vWF type A domain. The model of the complex indicates that the synergy region binds on the side of the beta-propeller domain. In support of this suggestion, mutagenesis of a prominent loop region on the side of the propeller identifies two residues (Tyr208 and Ile210) involved in recognition of the synergy region. Our data provide the first view of a complex between an integrin and a macromolecular ligand in solution, at a nominal resolution of approximately 10 A.
Highlights
Integrins are heterodimeric adhesion receptors with critical roles in development, cell migration, and survival [1, 2]
The scattering data suggest that the head region undergoes no gross conformational changes upon ligand binding but do lend support to a proposed outward movement of the hybrid domain in the  subunit
A number of issues concerning the structural basis of integrin-ligand binding are currently unresolved. (i) It is not known whether the binding of integrins to their native macromolecular ligands occurs by the same or by different mechanisms as that observed for RGD peptide mimics. (ii) The location of synergy binding sites on the integrin have not been pinpointed. (iii) It is unclear whether major conformational changes occur
Summary
Integrins are heterodimeric adhesion receptors with critical roles in development, cell migration, and survival [1, 2]. We have used solution x-ray scattering to visualize the head region of integrin ␣51 in an inactive (Ca2؉-occupied) state, and in complex with a fragment of fibronectin containing the RGD and synergy recognition sequences.
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