Crystal structure of a phosphoinositide phosphatase, MTMR2: Insights into myotubular myopathy and Charcot-Marie-Tooth syndrome
Crystal structure of a phosphoinositide phosphatase, MTMR2: Insights into myotubular myopathy and Charcot-Marie-Tooth syndrome
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DOI：
10.1016/s1097-2765(03)00486-6
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发表时间：
2003-12-01
期刊：
影响因子：
16
通讯作者：
Stuckey, JA
中科院分区：
文献类型：
--
作者：
Begley, MJ;Taylor, GS;Stuckey, JA
肌管蛋白相关蛋白是蛋白酪氨酸磷酸酶（PTP）的一个大的亚家族，其使D3-磷酸化的肌醇脂质去磷酸化。肌管蛋白家族成员的突变导致人类神经肌肉疾病肌管肌病和4 B型Charcot-Marie-Tooth综合征。该家族的代表性成员MTMR 2的晶体结构揭示了在PTP中结构独特的磷酸酶结构域。描述了一系列突变体，其表现出改变的酶活性，并提供了对磷酸肌醇底物的肌微管蛋白磷酸酶的特异性的了解。该结构还揭示了在肌管蛋白家族磷酸酶中发现的并被预测存在于类似于180种蛋白质中的P2P结构域是具有普列克底物蛋白同源性（PH）结构域折叠的较大基序的一部分。最后，MTMR 2结构将作为肌管蛋白家族其他成员的模型，并为理解这些蛋白质突变导致疾病的机制提供框架。
Myotubularin-related proteins are a large subfamily of protein tyrosine phosphatases (PTPs) that dephosphorylate D3-phosphorylated inositol lipids. Mutations in members of the myotubularin family cause the human neuromuscular disorders myotubular myopathy and type 4B Charcot-Marie-Tooth syndrome. The crystal structure of a representative member of this family, MTMR2, reveals a phosphatase domain that is structurally unique among PTPs. A series of mutants are described that exhibit altered enzymatic activity and provide insight into the specificity of myotubularin phosphatases toward phosphoinositide substrates. The structure also reveals that the GRAM domain, found in myotubularin family phosphatases and predicted to occur in similar to180 proteins, is part of a larger motif with a pleckstrin homology (PH) domain fold. Finally, the MTMR2 structure will serve as a model for other members of the myotubularin family and provide a framework for understanding the mechanism whereby mutations in these proteins lead to disease.