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

Structure
Predrag KukicMichele Vendruscolo

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.

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Citations

Apr 26, 2016·Chemical Reviews·Stephen Boulton, Giuseppe Melacini
Aug 27, 2016·Scientific Reports·Massimiliano BonomiMichele Vendruscolo
Apr 13, 2017·Journal of the American Chemical Society·Predrag KukicMichele Vendruscolo
Feb 12, 2020·Journal of Cellular and Molecular Medicine·Lingbo KongLiang Yan
Jun 12, 2021·The Journal of Physical Chemistry. B·Jinfeng HuangGiuseppe Melacini
Jul 14, 2017·Journal of Chemical Information and Modeling·Dániel DudolaZoltán Gáspári
Jan 31, 2020·Journal of Medicinal Chemistry·Yajun Zheng, Katerina Leftheris
Apr 17, 2020·Journal of Medicinal Chemistry·Hongzhao ShaoGiuseppe Melacini
Jul 18, 2018·Journal of the American Chemical Society·Stephen BoultonGiuseppe Melacini
May 11, 2019·Journal of Medicinal Chemistry·Stephen BoultonGiuseppe Melacini

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Methods Mentioned

BETA
nuclear magnetic resonance
NMR
X-ray

Software Mentioned

RAM
LINCS
Sparta
METAGUI
DSSP
GROMACS
PLUMED

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