title: Crystal structure of macrophage migration inhibitory factor (MIF), a glucocorticoid-induced regulator of cytokine production, reveals a unique architecture.
abstract: The mediator originally described as a macrophage migration inhibitory factor (MIF) has been identified recently to be a novel anterior pituitary hormone and the first protein to be released from immune cells upon stimulation with glucocorticoids. Once released, MIF acts to override or counter-regulate the immunosuppressive effects of glucocorticoids on cytokine production in vitro and on LPS lethality in vivo. MIF also has been described to catalyze a tautomerization reaction, suggesting that an enzymatic activity may underlie certain of its biological properties. The three-dimensional crystal structure of human MIF has been solved at 2.6A resolution. The X-ray crystal structure reveals MIF to be a trimer of identical subunits. Each monomer contains two antiparallel alpha-helices that pack against a four-stranded beta-sheet. The monomer has an additional two beta-strands that interact with the beta-sheets of adjacent subunits to form the interface between monomers. The three beta-sheets are arranged to form a barrel containing a solvent-accessible channel that runs through the center of the protein along a molecular three-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 hormones and suggests that this glucocorticoid-induced counter-regulatory hormone has a novel mechanism of action.
authors.affiliation: Department of Pharmacology, Yale University, New Haven, CT, USA.
authors.forename: E
authors.initials: E
authors.lastname: Lolis
authors.forename: R
authors.initials: R
authors.lastname: Bucala
mesh_terms: D000818:Animals; D003460:Crystallization; D018360:Crystallography, X-Ray; D006801:Humans; D008263:Macrophage Migration-Inhibitory Factors / Q000737:chemistry*; D011487:Protein Conformation; D017510:Protein Folding
chemical_list: D008263:Macrophage Migration-Inhibitory Factors