Regulation of the mitochondrial protein quality control factor VMS1

Abstract

Mitochondrial function is constantly threatened by damaging agents, including mitochondria‐derived reactive oxygen species. This stochastic burden damages mitochondria, which left unchecked leads to mitochondrial dysfunction. The detrimental consequences of mitochondrial dysfunction are highlighted by its presence in many human diseases including cancer, Parkinson's Disease, and diabetes. To prevent mitochondrial dysfunction, cells have evolved mitochondrial quality control mechanisms, which include protein degradation. A critical component in mitochondrial protein quality control degradation is the protein VCP/Cdc48‐associated Mitochondrial Stress‐responsive (Vms1), which together with Cdc48, translocates to mitochondria under stress. Through the action of Cdc48, an ATPase critical for ER‐associated degradation, Vms1 promotes the proteasomal degradation of proteins embedded in the mitochondrial outer membrane. Deletion of VMS1 results in oxidative stress that leads to a shortened lifespan in yeast and nematodes, which is highly suggestive of mitochondrial dysfunction. Mitochondrial localization of the Cdc48/Vms1 complex depends on a highly conserved Mitochondrial Targeting Domain (MTD), which is inhibited by an intramolecular interaction with the N‐terminal Leucine Rich Sequence (LRS) of Vms1 in unstressed conditions. We aimed to further our understanding of the stress‐responsive localization of Vms1 to mitochondria through structural and biochemical studies. Toward this goal we have: (1) identified a modified mitochondrial sphingolipid that is necessary and sufficient for Vms1 mitochondrial localization, and (2) determined the structure of Vms11–417 (2.7Å, 25% R‐free), which includes the MTD/LRS interaction. These data suggest a model in which the novel MTD fold binds the sphingolipid receptor head group in a pocket that is masked in the auto inhibited state by the LRS and becomes accessible following a conformational change. This model is being tested by structure‐based mutagenic, biochemical, and genetic experiments.Support or Funding InformationNIH GM115129AHA Postdoctoral Fellowship 14POST20380216