Structural and mechanistic insights into phospholipid transfer by Ups1-Mdm35 in mitochondria.
Structural and mechanistic insights into phospholipid transfer by Ups1-Mdm35 in mitochondria.
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DOI：
10.1038/ncomms8922
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发表时间：
2015-08-03
影响因子：
16.6
通讯作者：
Endo T
中科院分区：
文献类型：
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作者：
Watanabe Y;Tamura Y;Kawano S;Endo T
真核细胞被划分成膜结合的细胞器，其功能依赖于脂质运输以实现脂质的膜特异性组合物。在这里，我们专注于Ups 1-Mdm 35系统，它介导磷脂酸（PA）之间的外和内线粒体膜的转移，并确定了X射线结构的Mdm 35和Ups 1-Mdm 35与和没有PA。Ups 1-Mdm 35复合物构成具有深口袋和柔性Ω环盖的单个结构域。基于结构的突变分析表明，在口袋底部和Ω-环盖的碱性残基是重要的PA提取从膜后Ups 1结合。Ups 1与膜的结合通过Mdm 35的解离而增强。我们还表明，口袋入口周围的碱性残基是重要的Ups 1结合到膜和PA提取。这些结果为了解PA在线粒体膜间的转运机制提供了结构基础。 膜之间的磷脂运输对于维持膜结合细胞区室的结构完整性和功能至关重要。在这里，作者建立了线粒体外膜和内膜之间通过Ups 1-Mdm 35脂质转运复合物转运磷脂酸的结构基础。
Eukaryotic cells are compartmentalized into membrane-bounded organelles whose functions rely on lipid trafficking to achieve membrane-specific compositions of lipids. Here we focused on the Ups1–Mdm35 system, which mediates phosphatidic acid (PA) transfer between the outer and inner mitochondrial membranes, and determined the X-ray structures of Mdm35 and Ups1–Mdm35 with and without PA. The Ups1–Mdm35 complex constitutes a single domain that has a deep pocket and flexible Ω-loop lid. Structure-based mutational analyses revealed that a basic residue at the pocket bottom and the Ω-loop lid are important for PA extraction from the membrane following Ups1 binding. Ups1 binding to the membrane is enhanced by the dissociation of Mdm35. We also show that basic residues around the pocket entrance are important for Ups1 binding to the membrane and PA extraction. These results provide a structural basis for understanding the mechanism of PA transfer between mitochondrial membranes. Phospholipid trafficking between membranes is essential to maintain the structural integrity and function of membrane-bound cellular compartments. Here the authors establish the structural basis for transport of phosphatidic acid between the outer and inner membranes of the mitochondria by the Ups1–Mdm35 lipid-transport complex.