A 16-residue peptide fragment of macrophage migration inhibitory factor, MIF-(50-65), exhibits redox activity and has MIF-like biological functions
A 16-residue peptide fragment of macrophage migration inhibitory factor, MIF-(50-65), exhibits redox activity and has MIF-like biological functions
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DOI：
10.1074/jbc.m301735200
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发表时间：
2003-09-05
影响因子：
4.8
通讯作者：
Bernhagen, J
中科院分区：
文献类型：
--
作者：
Nguyen, MT;Beck, J;Bernhagen, J
巨噬细胞迁移抑制因子（Macrophage migration inhibitory factor， MIF）是一种参与宿主炎症反应的细胞因子。MIF的Cys-Xaa-Xaa-Cys （CXXC）基硫醇蛋白氧化还原酶活性与某些生物学功能有关。跨越巯基蛋白氧化还原酶的CXXC区域的肽保留了全长蛋白的一些生化特性。我们报道了横跨cxxc的MIF-(50-65)及其丝氨酸变体C57S/C60S-MIF-(50-65)的特征。在二硫化物介导的环化之后，MIF-(50-65)适应了与含β -环-57,60-[Asp(57), Dap(60)] MIF-(50-65)相似的β -旋构象。MIF（50 ~ 65）的氧化还原电位E′(0)为- 0.258 V，与谷胱甘肽和半胱氨酸形成混合二硫化物。MIF（50 ~ 65）具有体外氧化还原酶活性，而C57S/C60S-MIF-(50 ~ 65)没有。有趣的是，MIF-(50 - 65)表现出类似于MIF-的细胞活性。该肽具有糖皮质激素抑制和增殖增强活性，并刺激ERK1/2磷酸化。MIF-(50 - 65)及其变体与MIF结合蛋白JAB1结合，并提高p27（Kip1）的细胞水平。由于肽及其变体以相似的效率被内噬，序列50 - 65似乎足以满足MIF与jab1相关的作用，而其他活性则需要CXXC。cyclo57,60-[Asp57, Dap60] MIF-(5065)激活ERK1/2，表明cxxc依赖性二硫化物和β -turn的形成与活性诱导构象有关。我们得出结论，CXXC和序列50 - 65对MIF的活性至关重要。MIF-(50 - 65)是一个令人惊讶的短序列，具有MIF样功能，可能是MIF治疗的优秀分子模板。
Macrophage migration inhibitory factor (MIF) is a cytokine that participates in the host inflammatory response. A Cys-Xaa-Xaa-Cys (CXXC)-based thiol-protein oxidoreductase activity of MIF is associated with certain biological functions. Peptides spanning the CXXC region of thiol-protein oxidoreductases retain some biochemical properties of the full-length protein. We report on the characterization of CXXC-spanning MIF-(50-65) and its serine variant, C57S/C60S-MIF-(50-65). Following disulfide-mediated cyclization, MIF-(50-65) adapted a beta-turn conformation comparable with that of beta-turn-containing cyclo-57,60-[Asp(57), Dap(60)] MIF-(50-65). MIF( 50 - 65) had a redox potential E'(0) of - 0.258 V and formed mixed disulfides with glutathione and cysteine. MIF( 50 - 65) but not C57S/C60S-MIF-( 50 - 65) had oxidoreductase activity in vitro. Intriguingly, MIF-( 50 - 65) exhibited MIF- like cellular activities. The peptide but not its variant had glucocorticoid overriding and proliferation-enhancing activity and stimulated ERK1/2 phosphorylation. MIF-( 50 - 65) and its variant bound to the MIF-binding protein JAB1 and enhanced cellular levels of p27(Kip1). As the peptide and its variant were endocytosed at similar efficiency, sequence 50 - 65 appears sufficient for the JAB1-related effects of MIF, whereas other activities require CXXC. Cyclo-57,60-[ Asp57, Dap60] MIF-( 50 65) activated ERK1/2, indicating that CXXC-dependent disulfide and beta-turn formation is associated with an activity-inducing conformation. We conclude that CXXC and sequence 50 - 65 are critical for the activities of MIF. MIF-( 50 - 65) is a surprisingly short sequence with MIF-like functions that could be an excellent molecular template for MIF therapeutics.