Conformational changes in the endosomal sorting complex required for the transport III subunit Ist1 lead to distinct modes of ATPase Vps4 regulation

Jason Tan, Brian A. Davies, Johanna A. Payne, Linda M. Benson, David J Katzmann

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Intralumenal vesicle formation of the multivesicular body is a critical step in the delivery of endocytic cargoes to the lysosome for degradation. Endosomal sorting complex required for transport III (ESCRT-III) subunits polymerize on endosomal membranes to facilitate membrane budding away from the cytoplasm to generate these intralumenal vesicles. The ATPase Vps4 remodels and disassembles ESCRT-III, but the manner in which Vps4 activity is coordinated with ESCRT-III function remains unclear. Ist1 is structurally homologous to ESCRT-III subunits and has been reported to inhibit Vps4 function despite the presence of a microtubule-interacting and trafficking domain-interacting motif (MIM) capable of stimulating Vps4 in the context of other ESCRT-III subunits. Here we report that Ist1 inhibition of Vps4 ATPase activity involves two elements in Ist1: the MIM itself and a surface containing a conserved ELYC sequence. In contrast, the MI Minteraction, in concert with a more open conformation of the Ist1 core, resulted in stimulation of Vps4. Addition of the ESCRT-III subunit binding partner of Ist1, Did2, also converted Ist1 from an inhibitor to a stimulator of Vps4 ATPase activity. Finally, distinct regulation of Vps4 by Ist1 corresponded with altered ESCRT-III disassembly in vitro. Together, these data support a model in which Ist1-Did2 interactions during ESCRT-III polymerization coordinate Vps4 activity with the timing of ESCRT-III disassembly.

Original languageEnglish (US)
Pages (from-to)30053-30065
Number of pages13
JournalJournal of Biological Chemistry
Volume290
Issue number50
DOIs
StatePublished - Dec 11 2015

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Endosomal Sorting Complexes Required for Transport
Adenosine Triphosphatases
Multivesicular Bodies
Membranes
Conserved Sequence
Lysosomes
Microtubules
Polymerization
Conformations
Cytoplasm

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Conformational changes in the endosomal sorting complex required for the transport III subunit Ist1 lead to distinct modes of ATPase Vps4 regulation. / Tan, Jason; Davies, Brian A.; Payne, Johanna A.; Benson, Linda M.; Katzmann, David J.

In: Journal of Biological Chemistry, Vol. 290, No. 50, 11.12.2015, p. 30053-30065.

Research output: Contribution to journalArticle

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