甾醇氧化介导应激反应性Vms1易位至线粒体。
Sterol Oxidation Mediates Stress-Responsive Vms1 Translocation to Mitochondria.
作者信息
Nielson Jason R, Fredrickson Eric K, Waller T Cameron, Rendón Olga Zurita, Schubert Heidi L, Lin Zhenjian, Hill Christopher P, Rutter Jared
机构信息
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
出版信息
Mol Cell. 2017 Nov 16;68(4):673-685.e6. doi: 10.1016/j.molcel.2017.10.022.
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.
Vms1在应激反应时易位至受损的线粒体，随后其结合伴侣Cdc48有助于线粒体蛋白质稳态。Vms1的线粒体靶向由其保守的线粒体靶向结构域（MTD）介导，在无应激条件下，该结构域通过与Vms1富含亮氨酸序列（LRS）的分子内结合而受到抑制。在此，我们报道了Vms1的2.7埃晶体结构，该结构揭示LRS位于自抑制MTD的疏水凹槽中。我们还证明，氧化固醇麦角固醇过氧化物通过与MTD结合，以一种与LRS结合竞争的相互作用，对于Vms1定位于线粒体是必要且充分的。这些数据支持了一个模型，即应激的线粒体产生一种氧化固醇受体，该受体招募Vms1以支持线粒体蛋白质稳态。
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