Presequence-dependent folding ensures MrpL32 processing by the m-AAA protease in mitochondria
Presequence-dependent folding ensures MrpL32 processing by the m-AAA protease in mitochondria
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DOI：
10.1038/emboj.2011.169
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发表时间：
2011-07-06
期刊：
影响因子：
11.4
通讯作者：
Langer, Thomas
中科院分区：
文献类型：
--
作者：
Bonn, Florian;Tatsuta, Takashi;Langer, Thomas
m-AAA 蛋白酶在线粒体内膜中发挥双重功能：它们介导特定调节蛋白的加工并确保蛋白质质量控制，将错误折叠的多肽降解为肽。这些活性的丧失会导致几种神经退行性疾病中的神经元细胞死亡。然而，目前尚不清楚 m-AAA 蛋白酶如何在特定处理和完全降解之间进行选择。 m-AAA 蛋白酶的一个核心且保守的功能是核糖体亚基 MrpL32 的加工，它调节核糖体生物合成和呼吸复合物的形成。在这里，我们证明，包含保守的 CxxC-X-9-CxxC 序列基序的紧密折叠结构域的形成可以阻止从 N 末端开始的降解，并触发成熟 MrpL32 的释放。氧化应激会损害 MrpL32 的折叠，导致其被 m-AAA 蛋白酶降解并减少线粒体翻译。令人惊讶的是，MrpL32 折叠取决于其线粒体靶向序列。 MrpL32 的前序列辅助折叠需要在成熟发生之前完全导入 MrpL32 前体，因此解释了需要 m-AAA 蛋白酶进行后易位加工，而不是一般线粒体加工肽酶进行共易位裂解。 EMBO 杂志 (2011) 30, 2545-2556。 doi：10.1038/emboj.2011.169； 2011 年 5 月 24 日在线发布
m-AAA proteases exert dual functions in the mitochondrial inner membrane: they mediate the processing of specific regulatory proteins and ensure protein quality control degrading misfolded polypeptides to peptides. Loss of these activities leads to neuronal cell death in several neurodegenerative disorders. However, it is unclear how the m-AAA protease chooses between specific processing and complete degradation. A central and conserved function of the m-AAA protease is the processing of the ribosomal subunit MrpL32, which regulates ribosome biogenesis and the formation of respiratory complexes. Here, we demonstrate that the formation of a tightly folded domain harbouring a conserved CxxC-X-9-CxxC sequence motif halts degradation initiated from the N-terminus and triggers the release of mature MrpL32. Oxidative stress impairs folding of MrpL32, resulting in its degradation by the m-AAA protease and decreased mitochondrial translation. Surprisingly, MrpL32 folding depends on its mitochondrial targeting sequence. Presequence-assisted folding of MrpL32 requires the complete import of the MrpL32 precursor before maturation occurs and therefore explains the need for post-translocational processing by the m-AAA protease rather than co-translocational cleavage by the general mitochondrial processing peptidase. The EMBO Journal (2011) 30, 2545-2556. doi:10.1038/emboj.2011.169; Published online 24 May 2011