Crystal structure at 2.6-A resolution of human macrophage migration inhibitory factor.

Abstract

Macrophage migration inhibitory factor (MIF) was the first cytokine to be described, but for 30 years its role in the immune response remained enigmatic. In recent studies, MIF has been found to be a novel pituitary hormone and the first protein identified to be released from immune cells on glucocorticoid stimulation. Once secreted, MIF counterregulates the immunosuppressive effects of steroids and thus acts as a critical component of the immune system to control both local and systemic immune responses. We report herein the x-ray crystal structure of human MIF to 2.6-A resolution. The protein is a trimer of identical subunits. Each monomer contains two antiparallel a-helices that pack against a four-stranded a-sheet. The monomer has an additional two ,8-strands that interact with the a-sheets of adjacent subunits to form the interface between monomers. The three ,B-sheets are arranged to form a barrel containing a solvent-accessible channel that runs through the center of the protein along a molecular 3-fold axis. Electrostatic potential maps reveal that the channel has a positive potential, suggesting that it binds negatively charged molecules. The elucidated structure for MIF is unique among cytokines or hormonal mediators, and suggests that this counterregulator of glucocorticoid action participates in novel ligand-receptor interactions.

Macrophage migration inhibitory factor (MIF) promotes cell survival by activation of the Akt pathway and role for CSN5/JAB1 in the control of autocrine MIF activity

“…Macrophage migration inhibitory factor (MIF) is a conserved 12.5 kDa mediator that functionally belongs to the class of inflammatory cytokines, but has unique structural properties (Sun et al, 1996). MIF is secreted by immune and parenchymal cells upon inflammatory and stress stimulation, but is also expressed intracellularly in various cells, where it likely serves regulatory functions, that are mediated by protein-protein interactions (Calandra and Roger, 2003).…”

Molecular Interaction and Enzymatic Activity of Macrophage Migration Inhibitory Factor with Immunorelevant Peptides

“…X-ray crystallographic analysis of both human and rat recombinant MIF molecules showed a homotrimeric structure (13,14). However, MIF is predominantly expressed as the monomer (44%) and dimer (33%), whereas only a smaller fraction (23%) is assembled to form a trimer (15,16).…”

MIF from mussel: Coding sequence, phylogeny, polymorphism, 3D model and regulation of expression

“…Mg-MIF was superimposed onto human MIF (SwissProt 1gd0B) revealing 39.5% identity between the 2 structures. Mg-MIF possesses 2 a-helices and 6 b-sheets as reported for human MIF chain B model (Sun et al, 1996). Oxidoreductase catalytic site and tautomerase motif are conserved.…”

“…In addition to minor differences in amino acid replacements along the sequence, the major difference occurred on the length of the a-helix between tautomerase and oxidoreductase sites. This a-helix is 7 amino acids shorter in Mg-MIF compared to the human counterpart (Sun et al, 1996).…”

“…A phylogenetic tree was constructed by the Neighbor-Joining method after 1000 bootstrap iterations using CLC workbench 6.4. The protein structural model was developed using the SWISS-MODEL and the Swiss-PDB Viewer (Arnold et al, 2006) using the human model as comparison (Sun et al, 1996).…”