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Many questions about the significance of structural features of integrin αVβ3 with respect to its mechanism of activation remain. We have determined and re-refined crystal structures of the αVβ3 ectodomain linked to C-terminal coiled coils (αVβ3-AB) and four transmembrane (TM) residues in each subunit (αVβ3-1TM), respectively. The αV and β3 subunits with four and eight extracellular domains, respectively, are bent at knees between the integrin headpiece and lower legs, and the headpiece has the closed, low-affinity conformation. The structures differ in the occupancy of three metal-binding sites in the βI domain. Occupancy appears to be related to the pH of crystallization, rather than to the physiologic regulation of ligand binding at the central, metal ion-dependent adhesion site. No electron density was observed for TM residues and much of the αV linker. αVβ3-AB and αVβ 3-1TM demonstrate flexibility in the linker between their extracellular and TM domains, rather than the previously proposed rigid linkage. A previously postulated interface between the αV and β3 subunits at their knees was also not supported, because it lacks high-quality density, required rebuilding in αVβ 3-1TM, and differed markedly between αVβ 3-1TM and αVβ3-AB. Together with the variation in domain-domain orientation within their bent ectodomains between αVβ3-AB and αVβ 3-1TM, these findings are compatible with the requirement for large structural changes, such as extension at the knees and headpiece opening, in conveying activation signals between the extracellular ligand-binding site and the cytoplasm. © 2012 American Chemical Society.

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