A Novel Mechanism of Regulating the ATPase VPS4 by Its Cofactor LIP5 and the Endosomal Sorting Complex Required for Transport (ESCRT)-III Protein CHMP5
Abstract
Disassembly of the endosomal sorting complex required for transport (ESCRT) machinery from biological membranes is a critical final step in cellular processes that require the ESCRT function. This reaction is catalyzed by VPS4, an AAA-ATPase whose activity is tightly regulated by a host of proteins, including LIP5 and the ESCRT-III proteins. In this paper, we present structural and functional analyses of molecular interactions between human VPS4, LIP5, and the ESCRT-III proteins. The N-terminal domain of LIP5 (LIP5NTD) is required for LIP5-mediated stimulation of VPS4, and the ESCRT-III protein CHMP5 strongly inhibits the stimulation. Both of these observations are distinct from what was previously described for homologous yeast proteins. The crystal structure of LIP5NTD in complex with the MIT (microtubule-interacting and transport)-interacting motifs of CHMP5 and a second ESCRT-III protein, CHMP1B, was determined at 1 Å resolution. It reveals an ESCRT-III binding induced moderate conformational change in LIP5NTD, which results from insertion of a conserved CHMP5 tyrosine residue (Tyr182) at the core of LIP5NTD structure. Finally, mutation of Tyr182 partially relieves the inhibition displayed by CHMP5. Together, these results suggest a novel mechanism of VPS4 regulation in metazoans, where CHMP5 functions as a negative allosteric switch to control LIP5-mediated stimulation ofmore »
- Authors:
-
- Univ. of Michigan, Ann Arbor, MI (United States). Life Sciences Inst. Dept. of Biological Chemistry
- Univ. of Michigan, Ann Arbor, MI (United States). Life Sciences Inst.
- Publication Date:
- Research Org.:
- Univ. of Michigan, Ann Arbor, MI (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC); National Inst. of Health (NIH) (United States); Michigan Economic Development Corporation (United States); Michigan Technology Tri-Corridor (United States)
- OSTI Identifier:
- 1229905
- Grant/Contract Number:
- AC02-06CH11357; GM095769; 085P1000817
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Biological Chemistry
- Additional Journal Information:
- Journal Volume: 290; Journal Issue: 11; Journal ID: ISSN 0021-9258
- Publisher:
- American Society for Biochemistry and Molecular Biology
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; ATPase; Crystal Structure; Endosomal Sorting Complexes Required for Transport (ESCRT); Membrane Trafficking; Protein-Protein Interaction; CHMP5; LIP5; MIT-MIM; VPS4; Multivesicular Body
Citation Formats
Vild, Cody J., Li, Yan, Guo, Emily Z., Liu, Yuan, and Xu, Zhaohui. A Novel Mechanism of Regulating the ATPase VPS4 by Its Cofactor LIP5 and the Endosomal Sorting Complex Required for Transport (ESCRT)-III Protein CHMP5. United States: N. p., 2015.
Web. doi:10.1074/jbc.M114.616730.
Vild, Cody J., Li, Yan, Guo, Emily Z., Liu, Yuan, & Xu, Zhaohui. A Novel Mechanism of Regulating the ATPase VPS4 by Its Cofactor LIP5 and the Endosomal Sorting Complex Required for Transport (ESCRT)-III Protein CHMP5. United States. https://doi.org/10.1074/jbc.M114.616730
Vild, Cody J., Li, Yan, Guo, Emily Z., Liu, Yuan, and Xu, Zhaohui. Fri .
"A Novel Mechanism of Regulating the ATPase VPS4 by Its Cofactor LIP5 and the Endosomal Sorting Complex Required for Transport (ESCRT)-III Protein CHMP5". United States. https://doi.org/10.1074/jbc.M114.616730. https://www.osti.gov/servlets/purl/1229905.
@article{osti_1229905,
title = {A Novel Mechanism of Regulating the ATPase VPS4 by Its Cofactor LIP5 and the Endosomal Sorting Complex Required for Transport (ESCRT)-III Protein CHMP5},
author = {Vild, Cody J. and Li, Yan and Guo, Emily Z. and Liu, Yuan and Xu, Zhaohui},
abstractNote = {Disassembly of the endosomal sorting complex required for transport (ESCRT) machinery from biological membranes is a critical final step in cellular processes that require the ESCRT function. This reaction is catalyzed by VPS4, an AAA-ATPase whose activity is tightly regulated by a host of proteins, including LIP5 and the ESCRT-III proteins. In this paper, we present structural and functional analyses of molecular interactions between human VPS4, LIP5, and the ESCRT-III proteins. The N-terminal domain of LIP5 (LIP5NTD) is required for LIP5-mediated stimulation of VPS4, and the ESCRT-III protein CHMP5 strongly inhibits the stimulation. Both of these observations are distinct from what was previously described for homologous yeast proteins. The crystal structure of LIP5NTD in complex with the MIT (microtubule-interacting and transport)-interacting motifs of CHMP5 and a second ESCRT-III protein, CHMP1B, was determined at 1 Å resolution. It reveals an ESCRT-III binding induced moderate conformational change in LIP5NTD, which results from insertion of a conserved CHMP5 tyrosine residue (Tyr182) at the core of LIP5NTD structure. Finally, mutation of Tyr182 partially relieves the inhibition displayed by CHMP5. Together, these results suggest a novel mechanism of VPS4 regulation in metazoans, where CHMP5 functions as a negative allosteric switch to control LIP5-mediated stimulation of VPS4.},
doi = {10.1074/jbc.M114.616730},
journal = {Journal of Biological Chemistry},
number = 11,
volume = 290,
place = {United States},
year = {Fri Jan 30 00:00:00 EST 2015},
month = {Fri Jan 30 00:00:00 EST 2015}
}
Web of Science
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