| Structural highlights
Function
VMS1_YEAST Involved in the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway. Component of an evolutionarily conserved system for ubiquitin-mediated mitochondria-associated protein degradation (MAD), which is necessary to maintain mitochondrial, cellular, and organismal viability.[1] [2]
Publication Abstract from PubMed
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 A 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.
Sterol Oxidation Mediates Stress-Responsive Vms1 Translocation to Mitochondria.,Nielson JR, Fredrickson EK, Waller TC, Rendon OZ, Schubert HL, Lin Z, Hill CP, Rutter J Mol Cell. 2017 Nov 16;68(4):673-685.e6. doi: 10.1016/j.molcel.2017.10.022. PMID:29149595[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Heo JM, Livnat-Levanon N, Taylor EB, Jones KT, Dephoure N, Ring J, Xie J, Brodsky JL, Madeo F, Gygi SP, Ashrafi K, Glickman MH, Rutter J. A stress-responsive system for mitochondrial protein degradation. Mol Cell. 2010 Nov 12;40(3):465-80. doi: 10.1016/j.molcel.2010.10.021. PMID:21070972 doi:http://dx.doi.org/10.1016/j.molcel.2010.10.021
- ↑ Tran JR, Tomsic LR, Brodsky JL. A Cdc48p-associated factor modulates endoplasmic reticulum-associated degradation, cell stress, and ubiquitinated protein homeostasis. J Biol Chem. 2011 Feb 18;286(7):5744-55. doi: 10.1074/jbc.M110.179259. Epub 2010 , Dec 9. PMID:21148305 doi:http://dx.doi.org/10.1074/jbc.M110.179259
- ↑ Nielson JR, Fredrickson EK, Waller TC, Rendon OZ, Schubert HL, Lin Z, Hill CP, Rutter J. Sterol Oxidation Mediates Stress-Responsive Vms1 Translocation to Mitochondria. Mol Cell. 2017 Nov 16;68(4):673-685.e6. doi: 10.1016/j.molcel.2017.10.022. PMID:29149595 doi:http://dx.doi.org/10.1016/j.molcel.2017.10.022
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