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.
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. Here, 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 (Tyr(182)) at the core of LIP5NTD structure. Mutation of Tyr(182) 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.
authors: From the Life Sciences Institute and Department of Biological Chemistry, Medical School, University of Michigan, Ann Arbor, Michigan 48109.
authors: Cody J
authors: CJ
authors: Vild
authors: From the Life Sciences Institute and.
authors: Yan
authors: Y
authors: Li
authors: From the Life Sciences Institute and.
authors: Emily Z
authors: EZ
authors: Guo
authors: From the Life Sciences Institute and.
authors: Yuan
authors: Y
authors: Liu
authors: From the Life Sciences Institute and Department of Biological Chemistry, Medical School, University of Michigan, Ann Arbor, Michigan 48109 zhaohui@umich.edu.
authors: Zhaohui
authors: Z
authors: Xu
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D056827:Endosomal Sorting Complexes Required for Transport / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D060066:Protein Interaction Maps
chemical_list: C499838:CHMP5 protein, human; D056827:Endosomal Sorting Complexes Required for Transport; C499837:VTA1 protein, human; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities; C490304:VPS4B protein, human
keywords: ATPase; CHMP5; Crystal Structure; Endosomal Sorting Complexes Required for Transport (ESCRT); LIP5; MIT-MIM; Membrane Trafficking; Multivesicular Body; Protein-Protein Interaction; VPS4
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