Structure and dynamics of the integrin LFA-1 I-domain in the inactive state underlie its inside-out/outside-in signaling and allosteric mechanisms.


Type
Article
Change log
Authors
Kukic, Predrag 
Alvin Leung, Hoi Tik 
Bemporad, Francesco 
Aprile, Francesco A 
Kumita, Janet R 
Abstract

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 α 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.

Description
Keywords
Allosteric Regulation, Amino Acid Sequence, Lymphocyte Function-Associated Antigen-1, Molecular Dynamics Simulation, Molecular Sequence Data, Protein Structure, Tertiary, Signal Transduction
Journal Title
Structure
Conference Name
Journal ISSN
0969-2126
1878-4186
Volume Title
23
Publisher
Cell Press
Sponsorship
This study was supported by the Wellcome Trust and the BBSRC.