Identification of the N-terminal transmembrane domain of StarD7 and its importance for mitochondrial outer membrane localization and phosphatidylcholine transfer.
Identification of the N-terminal transmembrane domain of StarD7 and its importance for mitochondrial outer membrane localization and phosphatidylcholine transfer.
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DOI：
10.1038/s41598-017-09205-1
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发表时间：
2017-08-18
影响因子：
4.6
通讯作者：
Sugimoto H
中科院分区：
文献类型：
--
作者：
Horibata Y;Ando H;Satou M;Shimizu H;Mitsuhashi S;Shimizu Y;Itoh M;Sugimoto H
StarD 7促进磷脂酰胆碱（PC）转移到线粒体，并且对于线粒体稳态至关重要。然而，PC通过蛋白质转移的分子机制仍然知之甚少。在本文中，我们描述了一个推定的新的跨膜（TM）结构域的C-末端的靶向信号（MTS）序列在N-末端的StarD 7。在HEPA-1和HepG 2细胞中，StarD 7的成熟形式整合和/或结合到线粒体外膜（OMM）的外小叶上。缺乏TM结构域的StarD 7的截短形式分布在线粒体的内部空间中，并且当在StarD 7-KO HEPA-1细胞中重新表达时不能逆转线粒体异常，例如复合物形成和PC含量。野生型StarD 7的再表达可以补偿StarD 7-KO HEPA-1细胞的这些线粒体功能。StarD 7的前体形式在TM结构域中的Met 76和Ala 77以及Ala 77和Ala 78之间被切割以产生成熟形式。这些结果表明，StarD 7通过其N-末端TM结构域锚定到OMM上，并且C-末端START结构域可以延伸到细胞质中并且在ER-线粒体接触位点处在ER和OMM之间穿梭PC。
StarD7 facilitates phosphatidylcholine (PC) transfer to mitochondria, and is essential for mitochondrial homeostasis. However, the molecular mechanism for PC transfer by protein remains poorly understood. Herein, we describe a putative novel transmembrane (TM) domain C-terminal to the mitochondria-targeting signal (MTS) sequence at the N-terminus of StarD7. The mature form of StarD7 is integrated and/or associated onto the outer leaflet of the outer mitochondrial membrane (OMM) in HEPA-1 and HepG2 cells. A truncated form of StarD7 lacking the TM domain is distributed in the inner space of the mitochondria, and cannot reverse mitochondrial abnormalities, such as complex formation and PC content, when re-expressed in StarD7-KO HEPA-1 cells. Re-expression of wild StarD7 can compensate these mitochondrial functions of StarD7-KO HEPA-1 cells. The precursor form of StarD7 is cleaved between Met76 and Ala77, and Ala77 and Ala78 in the TM domain to produce the mature form. These results suggest that StarD7 is anchored onto the OMM through its N-terminal TM domain, and the C-terminal START domain may extend into the cytoplasm and shuttle PC between the ER and OMM at the ER-mitochondria contact sites.