Crystal structure of the yeast Sac1: implications for its phosphoinositide phosphatase function
Crystal structure of the yeast Sac1: implications for its phosphoinositide phosphatase function
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DOI：
10.1038/emboj.2010.57
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发表时间：
2010-05-05
期刊：
影响因子：
11.4
通讯作者：
Mao, Yuxin
中科院分区：
文献类型：
--
作者：
Manford, Andrew;Xia, Tian;Mao, Yuxin
Sac家族磷酸肌醇（PI）磷酸酶是基于CX 5 R（T/S）的酶的基本家族，涉及细胞功能的许多方面，如PI稳态、细胞信号传导和膜运输。几个Sac家族成员的基因缺失导致动物模型中的致死性，并且已经在人类遗传性疾病中发现了Sac 3基因的突变。在这项研究中，我们报告了这个家族的创始成员，酵母Sac 1的Sac磷酸酶结构域的晶体结构。2.0埃分辨率的结构表明，Sac结构域包括两个紧密堆积的亚结构域，一个新的N-末端亚结构域和PI磷酸酶催化亚结构域。该结构还显示出催化P环的显著构象和催化位点处的大的带正电荷的凹槽。这些发现表明其去磷酸化功能的不寻常机制。人类Fig 4/Sac 3的同源结构建模允许绘制几种疾病相关突变的图谱，并为理解人类疾病的分子机制提供了框架。The EMBO Journal（2010）29，1489-1498. doi：10.1038/doj.2010.57; 2010年4月13日在线发布
Sac family phosphoinositide (PI) phosphatases are an essential family of CX5R(T/S)-based enzymes, involved in numerous aspects of cellular function such as PI homeostasis, cellular signalling, and membrane trafficking. Genetic deletions of several Sac family members result in lethality in animal models and mutations of the Sac3 gene have been found in human hereditary diseases. In this study, we report the crystal structure of a founding member of this family, the Sac phosphatase domain of yeast Sac1. The 2.0 angstrom resolution structure shows that the Sac domain comprises of two closely packed sub-domains, a novel N-terminal sub-domain and the PI phosphatase catalytic sub-domain. The structure further shows a striking conformation of the catalytic P-loop and a large positively charged groove at the catalytic site. These findings suggest an unusual mechanism for its dephosphorylation function. Homology structural modeling of human Fig4/Sac3 allows the mapping of several disease-related mutations and provides a framework for the understanding of the molecular mechanisms of human diseases. The EMBO Journal (2010) 29, 1489-1498. doi:10.1038/emboj.2010.57; Published online 13 April 2010