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Sterol Oxidation Mediates Stress-Responsive Vms1 Translocation to Mitochondria
Jason R Nielson1, Eric K Fredrickson1, T Cameron Waller1
1Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Molecular Cell
|November 18, 2017
Summary
Vms1 protein targets damaged mitochondria by binding oxidized sterols, like ergosterol peroxide. This interaction releases Vms1
Area of Science:
- Cellular Biology
- Mitochondrial Biology
- Protein Homeostasis
Background:
- Vms1 protein is crucial for maintaining mitochondrial protein homeostasis.
- Vms1 localization to mitochondria is regulated by its mitochondrial targeting domain (MTD) and leucine-rich sequence (LRS).
- Under stress, Vms1 translocates to damaged mitochondria, where its partner Cdc48 aids in protein quality control.
Purpose of the Study:
- To elucidate the structural mechanism of Vms1 autoinhibition.
- To identify the molecular trigger for Vms1 mitochondrial translocation.
- To understand how Vms1 is recruited to stressed mitochondria.
Main Methods:
- X-ray crystallography to determine the structure of Vms1.
- Biochemical assays to investigate Vms1-ergosterol peroxide interactions.
- Cellular localization studies to confirm Vms1 recruitment to mitochondria.
Main Results:
- A 2.7 Å crystal structure revealed that the LRS inhibits the MTD by binding in a hydrophobic groove.
- Ergosterol peroxide was identified as a necessary and sufficient molecule for Vms1 mitochondrial localization.
- Ergosterol peroxide binding to the MTD competitively inhibits LRS binding, releasing Vms1 autoinhibition.
Conclusions:
- Stressed mitochondria generate oxidized sterols, such as ergosterol peroxide, which act as receptors.
- These sterols recruit Vms1 to damaged mitochondria by disrupting its autoinhibited state.
- This mechanism is vital for Vms1's role in maintaining mitochondrial protein homeostasis under stress.
Keywords:
ROS signalingS. cerevisiaebiochemistrylipid signalingliposomesmitochondrial quality controloxidative stressprotein degradationsterolsstructure-functionMore Related Videos
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