Predicted structure of MIF/CD74 and RTL1000/CD74 complexes

Roberto Meza-Romero, Gil Benedek, Lin Leng, Richard Bucala, Arthur Vandenbark

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Macrophage migration inhibitory factor (MIF) is a key cytokine in autoimmune and inflammatory diseases that attracts and then retains activated immune cells from the periphery to the tissues. MIF exists as a homotrimer and its effects are mediated through its primary receptor, CD74 (the class II invariant chain that exhibits a highly structured trimerization domain), present on class II expressing cells. Although a number of binding residues have been identified between MIF and CD74 trimers, their spatial orientation has not been established. Using a docking program in silico, we have modeled binding interactions between CD74 and MIF as well as CD74 and a competitive MIF inhibitor, RTL1000, a partial MHC class II construct that is currently in clinical trials for multiple sclerosis. These analyses revealed 3 binding sites on the MIF trimer that each were predicted to bind one CD74 trimer through interactions with two distinct 5 amino acid determinants. Surprisingly, predicted binding of one CD74 trimer to a single RTL1000 antagonist utilized the same two 5 residue determinants, providing strong suggestive evidence in support of the MIF binding regions on CD74. Taken together, our structural modeling predicts a new MIF(CD74)3 dodecamer that may provide the basis for increased MIF potency and the requirement for ~3-fold excess RTL1000 to achieve full antagonism.

Original languageEnglish (US)
Pages (from-to)249-255
Number of pages7
JournalMetabolic Brain Disease
Volume31
Issue number2
DOIs
StatePublished - Apr 1 2016

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Macrophage Migration-Inhibitory Factors
Binding Sites
Tissue
Cytokines
Amino Acids
Computer Simulation
Autoimmune Diseases
Multiple Sclerosis
Clinical Trials
invariant chain

Keywords

  • Binding residues
  • Inflammation
  • Molecular modeling
  • Protein interactions

ASJC Scopus subject areas

  • Clinical Neurology
  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Predicted structure of MIF/CD74 and RTL1000/CD74 complexes. / Meza-Romero, Roberto; Benedek, Gil; Leng, Lin; Bucala, Richard; Vandenbark, Arthur.

In: Metabolic Brain Disease, Vol. 31, No. 2, 01.04.2016, p. 249-255.

Research output: Contribution to journalArticle

Meza-Romero, Roberto ; Benedek, Gil ; Leng, Lin ; Bucala, Richard ; Vandenbark, Arthur. / Predicted structure of MIF/CD74 and RTL1000/CD74 complexes. In: Metabolic Brain Disease. 2016 ; Vol. 31, No. 2. pp. 249-255.
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