Vps4 Stimulatory Element of the Cofactor Vta1 Contacts the ATPase Vps4 α7 and α9 to Stimulate ATP Hydrolysis

Davies, Brian A.; Norgan, Andrew P.; Payne, Johanna A.; Schulz, Mary E.; Nichols, Micah D.; Tan, Jason Andrew; Xu, Zhaohui; Katzmann, David J.

doi:10.1074/jbc.m114.580696

Cited by 17 publications

(17 citation statements)

References 58 publications

(103 reference statements)

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“…The N-terminal domain of Vta1 (Vta1NTD) was not required for the basal stimulatory activity, but binding of the ESCRT-III proteins Did2 and Vps60 to Vta1NTD provided an additional level of Vps4 stimulation. Based on these results, a model was proposed where the unstructured linker of Vta1 acts to inhibit the function of VSL and this inhibition is relieved upon binding of ESCRT-III to Vta1NTD (51). To determine whether a similar mechanism is utilized in metazoans, we probed LIP5-mediated regulation of VPS4 ATPase activity and its modulation by the ESCRT-III proteins.…”

Section: Resultsmentioning

confidence: 99%

A Novel Mechanism of Regulating the ATPase VPS4 by Its Cofactor LIP5 and the Endosomal Sorting Complex Required for Transport (ESCRT)-III Protein CHMP5

Vild

Li²,

Guo³

et al. 2015

Journal of Biological Chemistry

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Background: LIP5 and ESCRT-III are regulators of VPS4 in biological processes that require the ESCRT function. Results: Structural and functional analyses of human VPS4, LIP5, and ESCRT-III interactions are presented. Conclusion: ESCRT-III protein CHMP5 inhibits LIP5-mediated VPS4 activation by inducing a moderate conformational change within LIP5. Significance: This study reveals important mechanistic differences in VPS4 regulation between fungi and metazoans.

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Section: Resultsmentioning

confidence: 99%

A Novel Mechanism of Regulating the ATPase VPS4 by Its Cofactor LIP5 and the Endosomal Sorting Complex Required for Transport (ESCRT)-III Protein CHMP5

Vild

Li²,

Guo³

et al. 2015

Journal of Biological Chemistry

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“…LIP5/Vta1 might stabilize the Vps4 hexamer through interactions that bridge adjacent subunits. This idea is supported by the identification of a Vps4 stimulatory element N-terminal to the VSL domain in yeast Vta1 124 that directly contacts the small AAA ATPase domain 125 , although such an arrangement has yet to be visualized. A crystal structure of a VSL complex with the Vps4 small AAA ATPase and β-domain suggests that Vta1 may function to stabilize inter-hexameric association 25 , although this model is not obviously consistent with the finding that Vta1-Vps4 complexes appear to be stable hexamers 106 .…”

Section: Regulation Of Hexamerizationmentioning

confidence: 99%

Meiotic Clade AAA ATPases: Protein Polymer Disassembly Machines

Monroe

Hill

2016

Journal of Molecular Biology

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Meiotic clade AAA ATPases, which were initially grouped on the basis of phylogenetic classification of their AAA ATPase cassette, include four relatively well characterized family members, Vps4, spastin, katanin, and fidgetin. These enzymes all function to disassemble specific polymeric protein structures, with Vps4 disassembling the ESCRT-III polymers that are central to the many membrane-remodeling activities of the ESCRT pathway, and spastin, katanin p60 and fidgetin affecting multiple aspects of cellular dynamics by severing microtubules. They share a common domain architecture that features an N-terminal MIT domain followed by a single AAA ATPase cassette. Meiotic clade AAA ATPases function as hexamers that can cycle between the active assembly and inactive monomers/dimers in a regulated process, and appear to disassemble their polymeric substrates by translocating subunits through the central pore of their hexameric ring. Recent studies with Vps4 have shown that nucleotide-induced asymmetry is a requirement for substrate binding to the pore loops, and that recruitment to the protein lattice via MIT domains also relieves auto-inhibition and primes the AAA ATPase cassettes for substrate binding. The most striking, unifying feature of meiotic clade AAA ATPases may be their MIT domain, which is a module that is found in a wide variety of proteins that localize to ESCRT-III polymers. Spastin also displays an adjacent microtubule-binding sequence, and the presence of both ESCRT-III and microtubule binding elements may underlie the recent findings that the ESCRT-III disassembly function of Vps4 and the microtubule-severing function of spastin, and potentially katanin and fidgetin, are highly coordinated.

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“…The ER-localized AAA ATPase Torsin is activated by lamin-associated polypeptide 1 (LAP1). Vps4 ATPase regulates the endosomal sorting complex required for transport (ESCRT) and is activated by ESCRT-III and the cofactor Vta1 (64). Finally, the activity of N-ethylmaleimide-sensitive factor (NSF) is stimulated by SNAP-SNARE complexes (65)(66)(67).…”

Section: Potential Model For the Role Of P97 Disease Mutants In Defecmentioning

confidence: 99%

Altered cofactor regulation with disease-associated p97/VCP mutations

Zhang

Gui

Zhang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

147

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Dominant mutations in p97/VCP (valosin-containing protein) cause a rare multisystem degenerative disease with varied phenotypes that include inclusion body myopathy, Paget's disease of bone, frontotemporal dementia, and amyotrophic lateral sclerosis. p97 disease mutants have altered N-domain conformations, elevated ATPase activity, and altered cofactor association. We have now discovered a previously unidentified disease-relevant functional property of p97 by identifying how the cofactors p37 and p47 regulate p97 ATPase activity. We define p37 as, to our knowledge, the first known p97-activating cofactor, which enhances the catalytic efficiency (k cat /K m ) of p97 by 11-fold. Whereas both p37 and p47 decrease the K m of ATP in p97, p37 increases the k cat of p97. In contrast, regulation by p47 is biphasic, with decreased k cat at low levels but increased k cat at higher levels. By deleting a region of p47 that lacks homology to p37 (amino acids 69-92), we changed p47 from an inhibitory cofactor to an activating cofactor, similar to p37. Our data suggest that cofactors regulate p97 ATPase activity by binding to the N domain. Induced conformation changes affect ADP/ATP binding at the D1 domain, which in turn controls ATPase cycling. Most importantly, we found that the D2 domain of disease mutants failed to be activated by p37 or p47. Our results show that cofactors play a critical role in controlling p97 ATPase activity, and suggest that lack of cofactorregulated communication may contribute to p97-associated disease pathogenesis.AAA ATPase | p97/VCP | MSP1 | p47 | steady-state kinetics

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Vps4 Stimulatory Element of the Cofactor Vta1 Contacts the ATPase Vps4 α7 and α9 to Stimulate ATP Hydrolysis

Cited by 17 publications

References 58 publications

A Novel Mechanism of Regulating the ATPase VPS4 by Its Cofactor LIP5 and the Endosomal Sorting Complex Required for Transport (ESCRT)-III Protein CHMP5

A Novel Mechanism of Regulating the ATPase VPS4 by Its Cofactor LIP5 and the Endosomal Sorting Complex Required for Transport (ESCRT)-III Protein CHMP5

Meiotic Clade AAA ATPases: Protein Polymer Disassembly Machines

Altered cofactor regulation with disease-associated p97/VCP mutations

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