title: Gremlin-1 C-Terminus Regulates Function of Macrophage Migration Inhibitory Factor (MIF).
abstract: OBJECTIVE
  The counterbalance of macrophage migration inhibitory factor (MIF) and Gremlin-1 is a useful tool to predict the acuity of coronary artery disease (CAD) and plaque stability. Gremlin1 is an endogenous antagonist of MIF and therefore influences plaque vulnerability. This study was designed to elucidate the mechanistic basis determining the biophysical binding of Gremlin-1 to MIF.
  
  
  METHODS
  An in silico model suggested that several charged C-terminal amino acids are crucial in mediating Gremlin-1/MIF-binding. We produced several single amino acid exchange mutants of Gremlin-1 by site-directed mutagenesis. These Gremlin-1 mutants were tested for their ability to reduce MIF effects on monocytes.
  
  
  RESULTS
  We observed that the critical element of the Gremlin-1 molecule for regulating MIF-induced chemotactic activity lies at the C-terminal region. A single amino acid exchange of an arginine to an alanine residue is sufficient to abolish the antagonistic effect of Gremlin-1 on MIF. Therefore, the Gremlin-1 mutant R172A failed to reduce MIF-induced monocyte differentiation into macrophages.
  
  
  CONCLUSIONS
  Gremlin-1 C-terminus is essential for antagonizing MIF effects. Our results could offer a novel strategy utilizing Gremlin-1 to target pro-inflammatory effects of MIF in various diseases.
authors.affiliation: Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, University of Tx00FC;bingen, Tx00FC;bingen, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Beck
authors.forename: Thomas
authors.initials: T
authors.lastname: Simmet
authors.forename: Iris
authors.initials: I
authors.lastname: Müller
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.forename: Meinrad
authors.initials: M
authors.lastname: Gawaz
mesh_terms: D000595:Amino Acid Sequence; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D002633:Chemotaxis; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D008958:Models, Molecular; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008263:Macrophage Migration-Inhibitory Factors; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human