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首页> 外文期刊>Journal of Molecular Biology >Structure of Human Acid Sphingomyelinase Reveals the Role of the Saposin Domain in Activating Substrate Hydrolysis
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Structure of Human Acid Sphingomyelinase Reveals the Role of the Saposin Domain in Activating Substrate Hydrolysis

机译：人类酸性鞘磷脂酶的结构揭示了Saposin域在激活底物水解中的作用

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摘要

Acid sphingomyelinase (ASM) is a lysosomal phosphodiesterase that catalyzes the hydrolysis of sphingomyelin to produce ceramide and phosphocholine. While other lysosomal sphingolipid hydrolases require a saposin activator protein for full activity, the ASM polypeptide incorporates a built-in N-terminal saposin domain and does not require an external activator protein. Here, we report the crystal structure of human ASM and describe the organization of the three main regions of the enzyme: the N-terminal saposin domain, the proline-rich connector, and the catalytic domain. The saposin domain is tightly associated along an edge of the large, bowl-shaped catalytic domain and adopts an open form that exposes a hydrophobic concave surface approximately 30 A from the catalytic center. The calculated electrostatic potential of the enzyme is electropositive at the acidic pH of the lysosome, consistent with the strict requirement for the presence of acidic lipids in target membranes. Docking studies indicate that sphingomyelin binds with the ceramide-phosphate group positioned at the binuclear zinc center and molecular dynamic simulations indicate that the intrinsic flexibility of the saposin domain is important for monomer-dimer exchange and for membrane interactions. Overall, ASM uses a combination of electrostatic and hydrophobic interactions to cause local disruptions of target bilayers in order to bring the lipid headgroup to the catalytic center in a membrane -bound reaction. (C) 2016 Elsevier Ltd. All rights reserved.
机译：酸性鞘磷脂酶（ASM）是一种溶酶体磷酸二酯酶，可催化鞘磷脂水解产生神经酰胺和磷酸胆碱。其他溶酶体鞘脂水解酶需要saposin激活蛋白才能发挥全部活性，而ASM多肽则整合了内置的N端saposin结构域，不需要外部激活蛋白。在这里，我们报告了人类ASM的晶体结构，并描述了该酶的三个主要区域的组织：N端saposin域，富含脯氨酸的连接器和催化域。 saposin结构域沿大的碗形催化结构域的边缘紧密结合，并采用开放形式，该结构暴露出距催化中心约30 A的疏水凹表面。酶的静电势在溶酶体的酸性pH下为正电，这与靶膜中存在酸性脂质的严格要求一致。对接研究表明鞘磷脂与位于双核锌中心的神经酰胺-磷酸基团结合，分子动力学模拟表明鞘脂蛋白域的固有柔性对于单体-二聚体交换和膜相互作用很重要。总的来说，ASM使用静电和疏水相互作用的组合来引起目标双层的局部破坏，以使脂头基团在膜结合反应中达到催化中心。 （C）2016 Elsevier Ltd.保留所有权利。

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