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The C-terminal region of the oxidoreductase MIA40 stabilizes its cytosolic precursor during mitochondrial import.
BMC Biology ( IF 4.4 ) Pub Date : 2020-08-06 , DOI: 10.1186/s12915-020-00824-1
Lena Maria Murschall 1 , Anne Gerhards 1 , Thomas MacVicar 2 , Esra Peker 1 , Lidwina Hasberg 1 , Stephan Wawra 3 , Thomas Langer 2, 4 , Jan Riemer 1, 4
Affiliation  

The mitochondrial intermembrane space (IMS) is home to proteins fulfilling numerous essential cellular processes, particularly in metabolism and mitochondrial function. All IMS proteins are nuclear encoded and synthesized in the cytosol and must therefore be correctly targeted and transported to the IMS, either through mitochondrial targeting sequences or conserved cysteines and the mitochondrial disulfide relay system. The mitochondrial oxidoreductase MIA40, which catalyzes disulfide formation in the IMS, is imported by the combined action of the protein AIFM1 and MIA40 itself. Here, we characterized the function of the conserved highly negatively charged C-terminal region of human MIA40. We demonstrate that the C-terminal region is critical during posttranslational mitochondrial import of MIA40, but is dispensable for MIA40 redox function in vitro and in intact cells. The C-terminal negatively charged region of MIA40 slowed import into mitochondria, which occurred with a half-time as slow as 90 min. During this time, the MIA40 precursor persisted in the cytosol in an unfolded state, and the C-terminal negatively charged region served in protecting MIA40 from proteasomal degradation. This stabilizing property of the MIA40 C-terminal region could also be conferred to a different mitochondrial precursor protein, COX19. Our data suggest that the MIA40 precursor contains the stabilizing information to allow for postranslational import of sufficient amounts of MIA40 for full functionality of the essential disulfide relay. We thereby provide for the first time mechanistic insights into the determinants controlling cytosolic surveillance of IMS precursor proteins.

中文翻译:

线粒体导入过程中,氧化还原酶MIA40的C端区域可稳定其胞质前体。

线粒体膜间空间(IMS)是满足许多重要细胞过程(特别是在代谢和线粒体功能方面)的蛋白质的所在地。所有IMS蛋白都是核编码并在细胞质中合成的,因此必须通过线粒体靶向序列或保守的半胱氨酸和线粒体二硫键中继系统正确靶向并转运至IMS。线粒体氧化还原酶MIA40催化IMS中的二硫键形成,是通过AIFM1和MIA40自身蛋白的联合作用而导入的。在这里,我们表征了人类MIA​​40保守的高度带负电的C端区域的功能。我们证明C-末端区域在MIA40的翻译后线粒体导入过程中至关重要,但对于MIA40的氧化还原功能在体外和完整细胞中都是必不可少的。MIA40的C端带负电的区域减慢了线粒体的导入速度,线粒体的发生时间仅为90分钟。在此期间,MIA40前体以未折叠状态持续存在于细胞质中,并且C端带负电的区域可保护MIA40免受蛋白酶体降解。MIA40 C端区域的这种稳定特性也可以赋予不同的线粒体前体蛋白COX19。我们的数据表明,MIA40前体包含稳定化信息,以允许翻译后导入足够量的MIA40,以使基本的二硫键继电器具有完整的功能。
更新日期:2020-08-06
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