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Sterol Oxidation Mediates Stress-Responsive Vms1 Translocation to Mitochondria.

ABSTRACT: 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.

SUBMITTER: Nielson JR

PROVIDER: S-EPMC5837041 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Sterol Oxidation Mediates Stress-Responsive Vms1 Translocation to Mitochondria.

Nielson Jason R JR Fredrickson Eric K EK Waller T Cameron TC Rendón Olga Zurita OZ Schubert Heidi L HL Lin Zhenjian Z Hill Christopher P CP Rutter Jared J

Molecular cell 20171101 4

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 a ...[more]

PMID: 29149595

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