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Proteins. 2014 Dec;82(12):3231-3240. doi: 10.1002/prot.24540. Epub 2014 Sep 25.

Talin-driven inside-out activation mechanism of platelet αIIbβ3 integrin probed by multimicrosecond, all-atom molecular dynamics simulations.

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Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1677, New York, New York 10029.
Allen and Frances Adler Laboratory of Blood and Vascular Biology, The Rockefeller University, 1230 York Avenue, Box 309, New York, New York 10065.
Contributed equally


Platelet aggregation is the consequence of the binding of extracellular bivalent ligands such as fibrinogen and von Willebrand factor to the high affinity, active state of integrin αIIbβ3. This state is achieved through a so-called "inside-out" mechanism characterized by the membrane-assisted formation of a complex between the F2 and F3 subdomains of intracellular protein talin and the integrin β3 tail. Here, we present the results of multi-microsecond, all-atom molecular dynamics simulations carried on the complete transmembrane (TM) and C-terminal (CT) domains of αIIbβ3 integrin in an explicit lipid-water environment, and in the presence or absence of the talin-1 F2 and F3 subdomains. These large-scale simulations provide unprecedented molecular-level insights into the talin-driven inside-out activation of αIIbβ3 integrin. Specifically, they suggest a preferred conformation of the complete αIIbβ3 TM/CT domains in a lipid-water environment, and testable hypotheses of key intermolecular interactions between αIIbβ3 integrin and the F2/F3 domains of talin-1. Notably, not only do these simulations give support to a stable left-handed reverse turn conformation of the αIIb juxtamembrane motif rather than a helical turn, but they raise the question as to whether TM helix separation is required for talin-driven integrin activation.


Anton; CHARMM; long-scale MD; membrane; molecular complex

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