Homologues of human macrophage migration inhibitory factor from a parasitic nematode. Gene cloning, protein activity, and crystal structure.
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.
Zang
Xingxing
X
Institute of Cell, Animal & Population Biology, University of Edinburgh, United Kingdom. xxzang@uclink4.berkeley.edu
Taylor
Paul
P
Wang
Ji Ming
JM
Meyer
David J
DJ
Scott
Alan L
AL
Walkinshaw
Malcolm D
MD
Maizels
Rick M
RM
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
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