title: Homologues of human macrophage migration inhibitory factor from a parasitic nematode. Gene cloning, protein activity, and crystal structure.
abstract: Cytokines are the molecular messengers of the vertebrate immune system, coordinating the local and systemic immune responses to infective organisms. We report here functional and structural data on cytokine-like proteins from a eukaryotic pathogen. Two homologues of the human cytokine macrophage migration inhibitory factor (MIF) have been isolated from the parasitic nematode Brugia malayi. Both molecules (Bm-MIF-1 and Bm-MIF-2) show parallel functions to human MIF. They are chemotactic for human monocytes and activate them to produce IL-8, TNF-alpha, and endogenous MIF. The human and nematode MIF homologues share a tautomerase enzyme activity, which is in each case abolished by the mutation of the N-terminal proline residue. The crystal structure of Bm-MIF-2 at 1.8-A resolution has been determined, revealing a trimeric assembly with an inner pore created by beta-stranded sheets from each subunit. Both biological activity and crystal structure reveal remarkable conservation between a human cytokine and its parasite counterpart despite the considerable phylogenetic divide among these organisms. The strength of the similarity implies that MIF-mediated pathways play an important role in nematode immune evasion strategies.
authors.affiliation: Institute of Cell, Animal & Population Biology, University of Edinburgh, United Kingdom. xxzang@uclink4.berkeley.edu
authors.forename: Xingxing
authors.initials: X
authors.lastname: Zang
authors.forename: Paul
authors.initials: P
authors.lastname: Taylor
authors.forename: Ji Ming
authors.initials: JM
authors.lastname: Wang
authors.forename: David J
authors.initials: DJ
authors.lastname: Meyer
authors.forename: Alan L
authors.initials: AL
authors.lastname: Scott
authors.forename: Malcolm D
authors.initials: MD
authors.lastname: Walkinshaw
authors.forename: Rick M
authors.initials: RM
authors.lastname: Maizels
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D017178:Brugia malayi / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D008263:Macrophage Migration-Inhibitory Factors / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000737:chemistry* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016209:Interleukin-8; C469748:MIF-1 protein, Brugia malayi; C469749:MIF-2 protein, Brugia malayi; D008263:Macrophage Migration-Inhibitory Factors; D015800:Protozoan Proteins; D014409:Tumor Necrosis Factor-alpha; D002118:Calcium