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Three-dimensional reconstruction of intact human integrin ?IIb?3: new implications for activation-dependent ligand binding.


ABSTRACT: Integrin ?IIb?3 plays a central role in hemostasis and thrombosis. We provide the first 3-dimensional reconstruction of intact purified ?IIb?3 in a nanodisc lipid bilayer. Unlike previous models, it shows that the ligand-binding head domain is on top, pointing away from the membrane. Moreover, unlike the crystal structure of the recombinant ectodomain, the lower legs are not parallel, straight, and adjacent. Rather, the ?IIb lower leg is bent between the calf-1 and calf-2 domains and the ?3 Integrin-Epidermal Growth Factor (I-EGF) 2 to 4 domains are freely coiled rather than in a cleft between the ?3 headpiece and the ?IIb lower leg. Our data indicate an important role for the region that links the distal calf-2 and ?-tail domains to their respective transmembrane (TM) domains in transmitting the conformational changes in the TM domains associated with inside-out activation.

SUBMITTER: Choi WS 

PROVIDER: S-EPMC3868924 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Three-dimensional reconstruction of intact human integrin αIIbβ3: new implications for activation-dependent ligand binding.

Choi Won-Seok WS   Rice William J WJ   Stokes David L DL   Coller Barry S BS  

Blood 20131017 26


Integrin αIIbβ3 plays a central role in hemostasis and thrombosis. We provide the first 3-dimensional reconstruction of intact purified αIIbβ3 in a nanodisc lipid bilayer. Unlike previous models, it shows that the ligand-binding head domain is on top, pointing away from the membrane. Moreover, unlike the crystal structure of the recombinant ectodomain, the lower legs are not parallel, straight, and adjacent. Rather, the αIIb lower leg is bent between the calf-1 and calf-2 domains and the β3 Inte  ...[more]

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