Talin-driven inside-out activation mechanism of platelet αIIbß3 integrin probed by multimicrosecond, all-atom molecular dynamics simulations.

ABSTRACT

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 αIIbß3. 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 ß3 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 αIIbß3 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 αIIbß3 integrin. Specifically, they suggest a preferred conformation of the complete αIIbß3 TM/CT domains in a lipid-water environment, and testable hypotheses of key intermolecular interactions between αIIbß3 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.