Structure of an integrin with an αI domain, complement receptor type 4

We report the structure of an integrin with an alpha I domain, alpha(X)beta(2), the complement receptor type 4. It was earlier expected that a fixed orientation between the aI domain and the beta-propeller domain in which it is inserted would be required for allosteric signal transmission. However, the alpha I domain is highly flexible, enabling two beta I domain conformational states to couple to three alpha I domain states, and greater accessibility for ligand recognition. Although alpha(X)beta(2) is bent similarly to integrins that lack alpha I domains, the terminal domains of the alpha-and beta-legs, calf-2 and beta-tail, are oriented differently than in alpha I-less integrins. Linkers extending to the transmembrane domains are unstructured. Previous mutations in the beta(2)-tail domain support the importance of extension, rather than a deadbolt, in integrin activation. The locations of further activating mutations and antibody epitopes show the critical role of extension, and conversion from the closed to the open headpiece conformation, in integrin activation. Differences among 10 molecules in crystal lattices provide unprecedented information on interdomain flexibility important for modelling integrin extension and activation. The EMBO Journal (2010) 29, 666-679. doi:10.1038/emboj.2009.367; Published online 24 December 2009