The high resolution crystal structure of the human tumor suppressor maspin reveals a novel conformational switch in the G-helix
The high resolution crystal structure of the human tumor suppressor maspin reveals a novel conformational switch in the G-helix
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DOI：
10.1074/jbc.m412043200
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发表时间：
2005-06-10
影响因子：
4.8
通讯作者：
Whisstock, JC
中科院分区：
文献类型：
--
作者：
Law, RHP;Irving, JA;Whisstock, JC
Maspin是一种蛇形蛋白，在包括乳腺癌和肺癌在内的一系列人类癌症中起肿瘤抑制作用。Maspin对发育至关重要，因为该基因的纯合缺失是致命的；然而，这种分子的确切生理作用尚不清楚。为了深入了解人类masmasin的功能，我们分别以2.1埃和2.8埃的分辨率确定了两种相似但非同构的晶体形式的晶体结构。结构表明，maspin采用天然蛇形折叠，反应中心环完全从A β -片中排出，与分子核心的接触最小，并表现出高度的灵活性。巨齿蛇蛋白同源物特有的埋藏盐桥导致D和E α -螺旋周围的区域出现不寻常的凸起，这一区域在其他巨齿蛇蛋白中被证明对辅助因子识别很重要。引人注目的是，结构数据显示，maspin能够在G α -螺旋内部和周围发生构象变化，在开放和封闭形式之间切换。这种变化决定了一个假定的辅因子结合表面的静电特性，并突出了这个区域可能是主蛋白功能的决定因素。masmasin的高分辨率晶体结构为阐明这一重要肿瘤抑制因子的功能机制提供了详细的分子框架。
Maspin is a serpin that acts as a tumor suppressor in a range of human cancers, including tumors of the breast and lung. Maspin is crucial for development, because homozygous loss of the gene is lethal; however, the precise physiological role of the molecule is unclear. To gain insight into the function of human maspin, we have determined its crystal structure in two similar, but nonisomorphous crystal forms, to 2.1- and 2.8-angstrom resolution, respectively. The structure reveals that maspin adopts the native serpin fold in which the reactive center loop is expelled fully from the A beta- sheet, makes minimal contacts with the core of the molecule, and exhibits a high degree of flexibility. A buried salt bridge unique to maspin orthologues causes an unusual bulge in the region around the D and E alpha- helices, an area of the molecule demonstrated in other serpins to be important for cofactor recognition. Strikingly, the structural data reveal that maspin is able to undergo conformational change in and around the G alpha- helix, switching between an open and a closed form. This change dictates the electrostatic character of a putative cofactor binding surface and highlights this region as a likely determinant of maspin function. The high resolution crystal structure of maspin provides a detailed molecular framework to elucidate the mechanism of function of this important tumor suppressor.