Structural and functional characterization of a secreted hookworm macrophage migration inhibitory factor (MIF) that interacts with the human MIF receptor CD74
Structural and functional characterization of a secreted hookworm macrophage migration inhibitory factor (MIF) that interacts with the human MIF receptor CD74
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DOI：
10.1074/jbc.m702950200
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发表时间：
2007-08-10
影响因子：
4.8
通讯作者：
Cappello, Michael
中科院分区：
文献类型：
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作者：
Cho, Yoonsang;Jones, Brian F.;Cappello, Michael
钩虫是一种寄生线虫，感染全球近10亿人，是贫血和营养不良的主要原因。我们假设钩虫通过产生特定的分子来积极操纵宿主的免疫反应，这些分子旨在促进幼虫阶段的感染和肠道内成虫的存活。已从钩虫锡兰钩虫（Ancylostoma ceylanicum）中克隆了编码人细胞因子巨噬细胞迁移抑制因子（MIF）的分泌型同源物的全长cDNA。重组AceMIF（rAceMIF）的三维晶体结构的解析揭示了整体结构的同源性，在人类和钩虫蛋白的互变异构酶位点的显着差异。使用体外互变异构酶活性、巨噬细胞迁移和与MIF受体CD 74结合的测定，比较人和钩虫MIF蛋白的相对生物活性。rAceMIF的活性不受配体ISO-1的抑制，该配体先前被确定为人MIF的催化位点的抑制剂。这些数据定义了AceMIF独特的免疫学、结构和功能特征，从而确立了选择性抑制钩虫细胞因子作为减少寄生虫存活和疾病发病机制的手段的潜力。
Hookworms, parasitic nematodes that infect nearly one billion people worldwide, are a major cause of anemia and malnutrition. We hypothesize that hookworms actively manipulate the host immune response through the production of specific molecules designed to facilitate infection by larval stages and adult worm survival within the intestine. A full-length cDNA encoding a secreted orthologue of the human cytokine, Macrophage Migration Inhibitory Factor (MIF) has been cloned from the hookworm Ancylostoma ceylanicum. Elucidation of the three-dimensional crystal structure of recombinant AceMIF (rAceMIF) revealed an overall structural homology with significant differences in the tautomerase sites of the human and hookworm proteins. The relative bioactivities of human and hookworm MIF proteins were compared using in vitro assays of tautomerase activity, macrophage migration, and binding to MIF receptor CD74. The activity of rAceMIF was not inhibited by the ligand ISO-1, which was previously determined to be an inhibitor of the catalytic site of human MIF. These data define unique immunological, structural, and functional characteristics of AceMIF, thereby establishing the potential for selectively inhibiting the hookworm cytokine as a means of reducing parasite survival and disease pathogenesis.