4.7 Article

Structure and Dynamics of the Integrin LFA-1 I-Domain in the Inactive State Underlie its Inside-Out/Outside-In Signaling and Allosteric Mechanisms

Journal

STRUCTURE
Volume 23, Issue 4, Pages 745-753

Publisher

CELL PRESS
DOI: 10.1016/j.str.2014.12.020

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Funding

  1. Wellcome Trust
  2. BBSRC

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Lymphocyte function-associated antigen 1 (LFA-1) is an integrin that transmits information in two directions across the plasma membrane of leukocytes, in so-called outside-in and inside-out signaling mechanisms. To investigate the structural basis of these mechanisms, we studied the conformational space of the apo I-domain using replica-averaged metadynamics simulations in combination with nuclear magnetic resonance chemical shifts. We thus obtained a free energy landscape that reveals the existence of three conformational substates of this domain. The three substates include conformations similar to existing crystallographic structures of the low-affinity I-domain, the inactive I-domain with an allosteric antagonist inhibitor bound underneath a helix 7, and an intermediate affinity state of the I-domain. The multiple substates were validated with residual dipolar coupling measurements. These results suggest that the presence of three substates in the apo I-domain enables the precise regulation of the binding process that is essential for the physiological function of LFA-1.

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