Crystal structure at 2.6-A resolution of human macrophage migration inhibitory factor.
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 angstrom resolution. The protein is 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 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.
Sun
H W
HW
Department of Pharmacology, Yale University, New Haven, CT 06510, USA.
Bernhagen
J
J
Bucala
R
R
Lolis
E
E
D000595:Amino Acid Sequence; D003196:Computer Graphics; D018360:Crystallography, X-Ray / Q000379:methods; D004926:Escherichia coli; D006801:Humans; D046911:Macromolecular Substances; D008263:Macrophage Migration-Inhibitory Factors / Q000096:biosynthesis / Q000737:chemistry* / Q000302:isolation & purification; D008958:Models, Molecular; D008961:Models, Structural; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000302:isolation & purification / Q000378:metabolism
D046911:Macromolecular Substances; D008263:Macrophage Migration-Inhibitory Factors; D011994:Recombinant Proteins