Dissection of the mitochondrial import and assembly pathway for human Tom40
Dissection of the mitochondrial import and assembly pathway for human Tom40
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DOI：
10.1074/jbc.m413816200
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发表时间：
2005-03-25
影响因子：
4.8
通讯作者：
Ryan, MT
中科院分区：
文献类型：
--
作者：
Humphries, AD;Streimann, IC;Ryan, MT
Tom40是线粒体外膜易位酶（TOM复合物）的通道形成亚基，对于蛋白质输入线粒体至关重要。Tom40在胞质溶胶中合成，并包含其线粒体靶向和组装的信息。真菌中的Tom40前体已经鉴定出许多稳定的进口中间体，第一个是与外膜的分选和组装机器（SAM）的关联。通过研究人Tom40的输入途径，我们已经能够阐明其输入的其他功能。我们确定，热休克蛋白90参与交付的Tom40前体线粒体在ATP依赖性的方式。然后，前体在其膜整合和组装之前与TOM复合物的外表面形成其第一稳定中间体。Tom40内进化保守区域的缺失破坏了TOM复合物中间体，并导致其在膜间空间中的新复合物处停滞，我们将其确定为哺乳动物SAM。与其真菌对应物不同，人类Tom40前体未被发现稳定地停滞在SAM中间体。尽管如此，我们表明，Tom40组装减少线粒体耗尽的人Sam50。这些研究结果进行了讨论的背景下，从真菌研究的当前模型。
Tom40 is the channel-forming subunit of the translocase of the mitochondrial outer membrane ( TOM complex), essential for protein import into mitochondria. Tom40 is synthesized in the cytosol and contains information for its mitochondrial targeting and assembly. A number of stable import intermediates have been identified for Tom40 precursors in fungi, the first being an association with the sorting and assembly machinery (SAM) of the outer membrane. By examining the import pathway of human Tom40, we have been able to elucidate additional features in its import. We identify that Hsp90 is involved in delivery of the Tom40 precursor to mitochondria in an ATP-dependent manner. The precursor then forms its first stable intermediate with the outer face of the TOM complex before its membrane integration and assembly. Deletion of an evolutionary conserved region within Tom40 disrupts the TOM complex intermediate and causes it to stall at a new complex in the intermembrane space that we identify to be the mammalian SAM. Unlike its fungal counterparts, the human Tom40 precursor is not found stably arrested at a SAM intermediate. Nevertheless, we show that Tom40 assembly is reduced in mitochondria depleted of human Sam50. These findings are discussed in context with current models from fungal studies.