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Mechanism of Vps4 hexamer function revealed by cryo-EM.


ABSTRACT: Vps4 is a member of AAA+ ATPase (adenosine triphosphatase associated with diverse cellular activities) that operates as an oligomer to disassemble ESCRT-III (endosomal sorting complex required for transport III) filaments, thereby catalyzing the final step in multiple ESCRT-dependent membrane remodeling events. We used electron cryo-microscopy to visualize oligomers of a hydrolysis-deficient Vps4 (vacuolar protein sorting-associated protein 4) mutant in the presence of adenosine 5'-triphosphate (ATP). We show that Vps4 subunits assemble into an asymmetric hexameric ring following an approximate helical path that sequentially stacks substrate-binding loops along the central pore. The hexamer is observed to adopt an open or closed ring configuration facilitated by major conformational changes in a single subunit. The structural transition of the mobile Vps4 subunit results in the repositioning of its substrate-binding loop from the top to the bottom of the central pore, with an associated translation of 33 Å. These structures, along with mutant-doping experiments and functional assays, provide evidence for a sequential and processive ATP hydrolysis mechanism by which Vps4 hexamers disassemble ESCRT-III filaments.

SUBMITTER: Su M 

PROVIDER: S-EPMC5392032 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Mechanism of Vps4 hexamer function revealed by cryo-EM.

Su Min M   Guo Emily Z EZ   Ding Xinqiang X   Li Yan Y   Tarrasch Jeffrey T JT   Brooks Charles L CL   Xu Zhaohui Z   Skiniotis Georgios G  

Science advances 20170414 4


Vps4 is a member of AAA<sup>+</sup> ATPase (adenosine triphosphatase associated with diverse cellular activities) that operates as an oligomer to disassemble ESCRT-III (endosomal sorting complex required for transport III) filaments, thereby catalyzing the final step in multiple ESCRT-dependent membrane remodeling events. We used electron cryo-microscopy to visualize oligomers of a hydrolysis-deficient Vps4 (vacuolar protein sorting-associated protein 4) mutant in the presence of adenosine 5'-tr  ...[more]

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