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New Insights into the Conformational Activation of Full-Length Integrin

By Tamara C. Bidone, Anirban Polley, Aleksander Durumeric, Tristan Driscoll, Daniel Iwamoto, David Calderwood, Martin A. Schwartz, Gregory A Voth

Posted 15 Oct 2017
bioRxiv DOI: 10.1101/203661

Integrin binding to extracellular matrix proteins is regulated by conformational transitions from closed, low affinity states to open, high affinity states. However, the pathways of integrin conformational activation remain incompletely understood. Here, by combining all-atom molecular dynamics simulation, coarse-graining, heterogeneous elastic network modeling, and experimental ligand binding measurements, we test the effect of integrin β mutations that destabilize the closed conformation. Our results support a “deadbolt” model of integrin activation, where extension of the headpiece is not coupled to leg separation, consistent with recent cryo-EM reconstructions of integrin intermediates. Moreover, our results are inconsistent with a “switchblade-like” mechanism. The data show that locally correlated atomistic motions are likely responsible for extension of integrin headpiece before separation of transmembrane legs, without persistence of these correlations across the entire protein. By combining modeling and simulation with experiment, this study provides new insight into the structural basis of full-length integrin activation.

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