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一种新型的跨膜间隙靶向信号在 Mia40 上对接半胱氨酸，以进行线粒体氧化折叠。

A novel intermembrane space-targeting signal docks cysteines onto Mia40 during mitochondrial oxidative folding.

机构信息

Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas, Heraklion, Crete, Greece.

出版信息

J Cell Biol. 2009 Dec 28;187(7):1007-22. doi: 10.1083/jcb.200905134. Epub 2009 Dec 21.

DOI:10.1083/jcb.200905134
PMID:20026652
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2806287/
Abstract

Mia40 imports Cys-containing proteins into the mitochondrial intermembrane space (IMS) by ensuring their Cys-dependent oxidative folding. In this study, we show that the specific Cys of the substrate involved in docking with Mia40 is substrate dependent, the process being guided by an IMS-targeting signal (ITS) present in Mia40 substrates. The ITS is a 9-aa internal peptide that (a) is upstream or downstream of the docking Cys, (b) is sufficient for crossing the outer membrane and for targeting nonmitochondrial proteins, (c) forms an amphipathic helix with crucial hydrophobic residues on the side of the docking Cys and dispensable charged residues on the other side, and (d) fits complementary to the substrate cleft of Mia40 via hydrophobic interactions of micromolar affinity. We rationalize the dual function of Mia40 as a receptor and an oxidase in a two step-specific mechanism: an ITS-guided sliding step orients the substrate noncovalently, followed by docking of the substrate Cys now juxtaposed to pair with the Mia40 active Cys.

摘要

Mia40 通过确保含半胱氨酸的蛋白质的 Cys 依赖性氧化折叠将其导入线粒体膜间隙（IMS）。在这项研究中，我们表明与 Mia40 对接的底物的特定半胱氨酸取决于底物，该过程由 Mia40 底物中存在的 IMS 靶向信号（ITS）指导。ITS 是一个 9 个氨基酸的内部肽段，（a）位于对接半胱氨酸的上游或下游，（b）足以穿过外膜并靶向非线粒体蛋白，（c）在对接半胱氨酸的一侧形成具有关键疏水性残基的两亲性螺旋，另一侧则是可有可无的带电荷残基，（d）通过与 Mia40 的底物裂隙的疏水相互作用以微摩尔亲和力互补结合。我们通过两步特异性机制来合理化 Mia40 作为受体和氧化酶的双重功能：ITS 引导的滑动步骤以非共价方式定位底物，然后是现在与 Mia40 活性半胱氨酸并列的底物半胱氨酸的对接。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7572/2806287/cbb948cb9079/JCB_200905134_RGB_Fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7572/2806287/137f1626392a/JCB_200905134_GS_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7572/2806287/5b1d486f5094/JCB_200905134_GS_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7572/2806287/b3cb639a7474/JCB_200905134_GS_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7572/2806287/43f1234003f1/JCB_200905134R_GS_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7572/2806287/33a6239188cd/JCB_200905134_RGB_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7572/2806287/cb3ede9f8a5e/JCB_200905134_GS_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7572/2806287/66f36a14a7c3/JCB_200905134_GS_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7572/2806287/4c0601dae4f6/JCB_200905134_GS_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7572/2806287/a4232efe498f/JCB_200905134_GS_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7572/2806287/cbb948cb9079/JCB_200905134_RGB_Fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7572/2806287/137f1626392a/JCB_200905134_GS_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7572/2806287/5b1d486f5094/JCB_200905134_GS_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7572/2806287/b3cb639a7474/JCB_200905134_GS_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7572/2806287/43f1234003f1/JCB_200905134R_GS_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7572/2806287/33a6239188cd/JCB_200905134_RGB_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7572/2806287/cb3ede9f8a5e/JCB_200905134_GS_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7572/2806287/66f36a14a7c3/JCB_200905134_GS_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7572/2806287/4c0601dae4f6/JCB_200905134_GS_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7572/2806287/a4232efe498f/JCB_200905134_GS_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7572/2806287/cbb948cb9079/JCB_200905134_RGB_Fig10.jpg

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