Crystal structure at 2.6-angstrom resolution of human macrophage migration inhibitory factor
Crystal structure at 2.6-angstrom resolution of human macrophage migration inhibitory factor
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DOI：
10.1073/pnas.93.11.5191
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发表时间：
1996-05-28
影响因子：
11.1
通讯作者：
Lolis, E
中科院分区：
文献类型：
--
作者：
Sun, HW;Bernhagen, J;Lolis, E
巨噬细胞移动抑制因子(MIF)是第一个被描述的细胞因子，但30年来它在免疫反应中的作用仍然是个谜。最近的研究发现，MIF是一种新的垂体激素，也是第一个被发现在糖皮质激素刺激下从免疫细胞释放的蛋白质。MIF一旦分泌，就能逆转类固醇的免疫抑制作用，从而成为免疫系统的关键组成部分，控制局部和全身的免疫反应。在此，我们报道了人MIF的2.6埃分辨率的X射线晶体结构。这种蛋白质是由相同亚基组成的三聚体。每个单体都含有两个反平行的α-螺旋，它们围绕着一个四链的β-折叠。该单体还有另外两条β-链，它们与相邻亚基的β-链相互作用，形成单体之间的界面。这三个β-折叠被安排成一个桶，其中包含一个溶剂可访问的通道，该通道沿着分子三重轴穿过蛋白质的中心。静电势图显示该通道具有正势，表明它结合了带负电荷的分子。已阐明的MIF结构在细胞因子或激素介质中是独一无二的，表明这种糖皮质激素作用的反向调节因子参与了新的配体-受体相互作用。
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.