Nanosecond Dynamics Regulate the MIF-Induced Activity of CD74

Angew Chem Int Ed Engl. 2018 Jun 11;57(24):7116-7119. doi: 10.1002/anie.201803191. Epub 2018 May 9.

Abstract

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.

Keywords: MIF; allosteric sites; long-range communication; protein dynamics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Site
  • Antigens, Differentiation, B-Lymphocyte / chemistry
  • Antigens, Differentiation, B-Lymphocyte / metabolism*
  • Histocompatibility Antigens Class II / chemistry
  • Histocompatibility Antigens Class II / metabolism*
  • Humans
  • Inflammation / metabolism
  • Intramolecular Oxidoreductases / chemistry
  • Intramolecular Oxidoreductases / metabolism*
  • Macrophage Migration-Inhibitory Factors / chemistry
  • Macrophage Migration-Inhibitory Factors / metabolism*
  • Molecular Dynamics Simulation
  • Protein Conformation, beta-Strand

Substances

  • Antigens, Differentiation, B-Lymphocyte
  • Histocompatibility Antigens Class II
  • Macrophage Migration-Inhibitory Factors
  • invariant chain
  • Intramolecular Oxidoreductases
  • MIF protein, human