Crystal structure of ?5?1 integrin ectodomain: atomic details of the fibronectin receptor.

ABSTRACT: Integrin ?5?1 is a major cellular receptor for the extracellular matrix protein fibronectin and plays a fundamental role during mammalian development. A crystal structure of the ?5?1 integrin headpiece fragment bound by an allosteric inhibitory antibody was determined at a 2.9-Å resolution both in the absence and presence of a ligand peptide containing the Arg-Gly-Asp (RGD) sequence. The antibody-bound ?1 chain accommodated the RGD ligand with very limited structural changes, which may represent the initial step of cell adhesion mediated by nonactivated integrins. Furthermore, a molecular dynamics simulation pointed to an important role for Ca(2+) in the conformational coupling between the ligand-binding site and the rest of the molecule. The RGD-binding pocket is situated at the center of a trenchlike exposed surface on the top face of ?5?1 devoid of glycosylation sites. The structure also enabled the precise prediction of the acceptor residue for the auxiliary synergy site of fibronectin on the ?5 subunit, which was experimentally confirmed by mutagenesis and kinetic binding assays.

SUBMITTER: Nagae M 

PROVIDER: S-EPMC3317794 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature