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Nanosecond Dynamics Regulate the MIF‐Induced Activity of CD74
Author(s) -
Pantouris Georgios,
Ho Junming,
Shah Dilip,
Syed Mansoor Ali,
Leng Lin,
Bhandari Vineet,
Bucala Richard,
Batista Victor S.,
Loria J. Patrick,
Lolis Elias J.
Publication year - 2018
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201803191
Subject(s) - macrophage migration inhibitory factor , cd74 , allosteric regulation , molecular dynamics , chemistry , microsecond , biophysics , inflammation , stereochemistry , biochemistry , biology , immunology , enzyme , cytokine , computational chemistry , in vitro , physics , astronomy , cytotoxic t cell , mhc class i
Macrophage migration inhibitory factor (MIF) activates CD74, which leads to severe disorders including inflammation, autoimmune diseases and cancer under pathological conditions. Molecular dynamics (MD) simulations up to one microsecond revealed dynamical correlation between a residue located at the opening of one end of the MIF solvent channel, previously thought to be a consequence of homotrimerization, and residues in a distal region responsible for CD74 activation. Experiments verified the allosteric regulatory site and identified a pathway to this site via the MIF β‐strands. The reported findings provide fundamental insights on a dynamic mechanism that controls the MIF‐induced activation of CD74.