Format

Send to

Choose Destination
Mol Cell. 2017 Nov 16;68(4):673-685.e6. doi: 10.1016/j.molcel.2017.10.022.

Sterol Oxidation Mediates Stress-Responsive Vms1 Translocation to Mitochondria.

Author information

1
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
2
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.
3
Department of Medicinal Chemistry, University of Utah College of Pharmacy, Salt Lake City, UT 84112, USA.
4
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA. Electronic address: hill@biochem.utah.edu.
5
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. Electronic address: rutter@biochem.utah.edu.

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.

KEYWORDS:

ROS signaling; S. cerevisiae; biochemistry; lipid signaling; liposomes; mitochondrial quality control; oxidative stress; protein degradation; sterols; structure-function

PMID:
29149595
PMCID:
PMC5837041
DOI:
10.1016/j.molcel.2017.10.022
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center