Crystal Structure of the Extracellular Segment of Integrin αVβ3 in Complex with an Arg-Gly-Asp Ligand

Abstract

The structural basis for the divalent cation-dependent binding of heterodimeric alphabeta integrins to their ligands, which contain the prototypical Arg-Gly-Asp sequence, is unknown. Interaction with ligands triggers tertiary and quaternary structural rearrangements in integrins that are needed for cell signaling. Here we report the crystal structure of the extracellular segment of integrin alphaVbeta3 in complex with a cyclic peptide presenting the Arg-Gly-Asp sequence. The ligand binds at the major interface between the alphaV and beta3 subunits and makes extensive contacts with both. Both tertiary and quaternary changes are observed in the presence of ligand. The tertiary rearrangements take place in betaA, the ligand-binding domain of beta3; in the complex, betaA acquires two cations, one of which contacts the ligand Asp directly and the other stabilizes the ligand-binding surface. Ligand binding induces small changes in the orientation of alphaV relative to beta3.

Phagocytosis and remodeling of collagen matrices

“…The α2β1 integrin binds to the GFOGER sequence in native collagen type I and does not bind to denatured collagen type I [60,62,[63][64][65]. The αvβ3 integrin binds to denatured collagen type I almost exclusively via matricryptic RGD sequences that are exposed upon denaturation and unwinding of the triple helix [59,61,[66][67][68]. In our continuing studies to elucidate a mechanistic basis for the results observed, α1β1 and α2β1 in response to native collagen, and αvβ3 in response to denatured collagen and RGD-dependent events, initiate the processes involved in the observations reported (unpublished data).…”

Structural and mechanical functions of integrins

“…extended with a closed headpiece (high affinity); (3) ligand occupied, i.e. extended with an open headpiece (Xiong et al 2001(Xiong et al , 2002Shimaoka et al 2003;Xiao et al 2004). At the present time, two models are proposed to describe the process of integrin activation: the 'deadbolt' model and the 'switchblade' model (Xiong et al 2003;Luo et al 2007).…”

Integrin‐dependent pathologies

“…Recently, the crystal structure of free and ligand-bound extracellular domains of the αvβ 3 -integrin heterodimer has been solved [19]. This data combined with NMR and electron-microscopic imaging have suggested that the integrin heterodimeric receptor behaves as an allosteric switch between a freely diffusing plasma membrane protein and a bivalent linker protein, binding simultaneously to extracellular ligands and cytoplasmic adaptor proteins [4,20,21].…”

“…(B) The tension-dependent organization of the actin cytoskeleton and the differential integrin dynamics results in a predictable focal adhesion behaviour that includes high-stability integrin clusters (avidity increase) at the cell front and strong, plastic adhesions in the back of the cell. Fast integrin turnover is illustrated by circular arrows; polarized integrin turnover in sliding focal contacts is illustrated by a circular-straight arrow; immobilized integrins in focal complexes are illustrated by vertical arrows onto the membrane proximal domains, such that the respective α-and β-transmembrane domains would lay in close proximity [19]. Furthermore, this closed, tightly packed conformation is stabilized by electrostatic interactions (salt bridge) in the membraneproximal cytoplasmic tail regions of the respective α-and β-subunits [20,23].…”