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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

Journal Article · · Journal of Biological Chemistry
 [1];  [2];  [2];  [2];  [1]
  1. Univ. of Michigan, Ann Arbor, MI (United States). Life Sciences Inst. Dept. of Biological Chemistry
  2. Univ. of Michigan, Ann Arbor, MI (United States). Life Sciences Inst.

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.

Research Organization:
Univ. of Michigan, Ann Arbor, MI (United States)
Sponsoring Organization:
USDOE Office of Science (SC); National Inst. of Health (NIH) (United States); Michigan Economic Development Corporation (United States); Michigan Technology Tri-Corridor (United States)
Grant/Contract Number:
AC02-06CH11357; GM095769; 085P1000817
OSTI ID:
1229905
Journal Information:
Journal of Biological Chemistry, Vol. 290, Issue 11; ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular BiologyCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 26 works
Citation information provided by
Web of Science

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Cited By (5)

Protein–protein interactions in AQP regulation – biophysical characterization of AQP0–CaM and AQP2–LIP5 complex formation journal January 2018
The role of VPS4 in ESCRT-III polymer remodeling journal February 2019
Structural Insights into AQP2 Targeting to Multivesicular Bodies journal October 2019
Aquaporin Protein-Protein Interactions journal October 2017
Plant and Mammal Aquaporins: Same but Different journal February 2018