Crystal structure of a membrane-bound O-acyltransferase,Nature

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Crystal structure of a membrane-bound O-acyltransferase
Nature ( IF 50.5 ) Pub Date : 2018-10-01 , DOI: 10.1038/s41586-018-0568-2
Dan Ma ₁ , Zhizhi Wang ₁ , Christopher N Merrikh ₂ , Kevin S Lang ₂ , Peilong Lu ₃ , Xin Li _{1,

4} , Houra Merrikh _{2,

5} , Zihe Rao _{4,

6,

7,

8,

9} , Wenqing Xu _{1,

6}

Affiliation

Membrane-bound O-acyltransferases (MBOATs) are a superfamily of integral transmembrane enzymes that are found in all kingdoms of life1. In bacteria, MBOATs modify protective cell-surface polymers. In vertebrates, some MBOAT enzymes—such as acyl-coenzyme A:cholesterol acyltransferase and diacylglycerol acyltransferase 1—are responsible for lipid biosynthesis or phospholipid remodelling2,3. Other MBOATs, including porcupine, hedgehog acyltransferase and ghrelin acyltransferase, catalyse essential lipid modifications of secreted proteins such as Wnt, hedgehog and ghrelin, respectively4–10. Although many MBOAT proteins are important drug targets, little is known about their molecular architecture and functional mechanisms. Here we present crystal structures of DltB, an MBOAT responsible for the d-alanylation of cell-wall teichoic acid in Gram-positive bacteria11–16, both alone and in complex with the d-alanyl donor protein DltC. DltB contains a ring of 11 peripheral transmembrane helices, which shield a highly conserved extracellular structural funnel extending into the middle of the lipid bilayer. The conserved catalytic histidine residue is located at the bottom of this funnel and is connected to the intracellular DltC through a narrow tunnel. Mutation of either the catalytic histidine or the DltC-binding site of DltB abolishes the d-alanylation of lipoteichoic acid and sensitizes the Gram-positive bacterium Bacillus subtilis to cell-wall stress, which suggests cross-membrane catalysis involving the tunnel. Structure-guided sequence comparison among DltB and vertebrate MBOATs reveals a conserved structural core and suggests that MBOATs from different organisms have similar catalytic mechanisms. Our structures provide a template for understanding structure–function relationships in MBOATs and for developing therapeutic MBOAT inhibitors.Crystal structures of DltB, a bacterial membrane-bound O-acyltransferase, are reported both alone and in complex with the d-alanyl donor protein DltC.

中文翻译：

膜结合 O-酰基转移酶的晶体结构

膜结合 O-酰基转移酶 (MBOAT) 是完整跨膜酶的超家族，存在于所有生命王国中 1。在细菌中，MBOAT 修饰保护性细胞表面聚合物。在脊椎动物中，一些 MBOAT 酶——例如酰基辅酶 A：胆固醇酰基转移酶和二酰甘油酰基转移酶 1——负责脂质生物合成或磷脂重塑 2, 3。其他 MBOAT，包括豪猪、刺猬酰基转移酶和生长素释放肽酰基转移酶，分别催化 Wnt、刺猬和生长素释放肽等分泌蛋白的必需脂质修饰 4-10。尽管许多 MBOAT 蛋白是重要的药物靶点，但对其分子结构和功能机制知之甚少。在这里，我们介绍 DltB 的晶体结构，负责革兰氏阳性细菌中细胞壁磷壁酸的 d-丙氨酰化的 MBOAT11-16，既单独使用又与 d-丙氨酰供体蛋白 DltC 复合。DltB 包含一个由 11 个外周跨膜螺旋组成的环，它屏蔽了一个延伸到脂质双层中间的高度保守的细胞外结构漏斗。保守的催化组氨酸残基位于该漏斗的底部，并通过狭窄的隧道连接到细胞内 DltC。DltB 的催化组氨酸或 DltC 结合位点的突变会消除脂磷壁酸的 d-丙氨酰化作用，并使革兰氏阳性细菌枯草芽孢杆菌对细胞壁应力敏感，这表明涉及隧道的跨膜催化作用。DltB 和脊椎动物 MBOAT 之间的结构导向序列比较揭示了一个保守的结构核心，并表明来自不同生物体的 MBOAT 具有相似的催化机制。我们的结构为理解 MBOAT 中的结构-功能关系和开发治疗性 MBOAT 抑制剂提供了一个模板。DltB（一种细菌膜结合的 O-酰基转移酶）的晶体结构被单独和与 d-丙氨酰供体蛋白 DltC 复合报道。

更新日期：2018-10-01

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