Sterol Oxidation Mediates Stress-Responsive Vms1 Translocation to Mitochondria.,Molecular Cell

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Sterol Oxidation Mediates Stress-Responsive Vms1 Translocation to Mitochondria.
Molecular Cell ( IF 14.5 ) Pub Date : 2017-11-16 , DOI: 10.1016/j.molcel.2017.10.022
Jason R Nielson ₁ , Eric K Fredrickson ₁ , T Cameron Waller ₁ , Olga Zurita Rendón ₂ , Heidi L Schubert ₁ , Zhenjian Lin ₃ , Christopher P Hill ₁ , Jared Rutter ₂

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Vms1 translocates to damaged mitochondria in response to stress, whereupon its binding partner, Cdc48, contributes to mitochondrial protein homeostasis. Mitochondrial targeting of Vms1 is mediated by its conserved mitochondrial targeting domain (MTD), which, in unstressed conditions, is inhibited by intramolecular binding to the Vms1 leucine-rich sequence (LRS). Here, we report a 2.7 Å crystal structure of Vms1 that reveals that the LRS lies in a hydrophobic groove in the autoinhibited MTD. We also demonstrate that the oxidized sterol, ergosterol peroxide, is necessary and sufficient for Vms1 localization to mitochondria, through binding the MTD in an interaction that is competitive with binding to the LRS. These data support a model in which stressed mitochondria generate an oxidized sterol receptor that recruits Vms1 to support mitochondrial protein homeostasis.

中文翻译：

甾醇氧化介导应激反应性 Vms1 易位至线粒体。

Vms1 在应激反应中易位至受损线粒体，其结合伙伴 Cdc48 有助于线粒体蛋白稳态。 Vms1 的线粒体靶向是由其保守的线粒体靶向结构域 (MTD) 介导的，在无应激条件下，该结构域会受到与 Vms1 富含亮氨酸序列 (LRS) 的分子内结合的抑制。在这里，我们报道了 Vms1 的 2.7 Å 晶体结构，揭示了 LRS 位于自抑制 MTD 的疏水凹槽中。我们还证明，氧化甾醇（过氧化麦角甾醇）对于 Vms1 定位到线粒体来说是必要且充分的，通过与 MTD 的结合，这种相互作用与与 LRS 的结合具有竞争性。这些数据支持一个模型，其中应激的线粒体会产生氧化甾醇受体，该受体招募 Vms1 以支持线粒体蛋白质稳态。

更新日期：2017-11-16

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