PT  - JOURNAL ARTICLE
AU  - Su, Min
AU  - Guo, Emily Z.
AU  - Ding, Xinqiang
AU  - Li, Yan
AU  - Tarrasch, Jeffrey T.
AU  - Brooks, Charles L.
AU  - Xu, Zhaohui
AU  - Skiniotis, Georgios
TI  - Mechanism of Vps4 hexamer function revealed by cryo-EM
AID  - 10.1126/sciadv.1700325
DP  - 2017 Apr 01
TA  - Science Advances
PG  - e1700325
VI  - 3
IP  - 4
4099  - http://advances.sciencemag.org/content/3/4/e1700325.short
4100  - http://advances.sciencemag.org/content/3/4/e1700325.full
SO  - Sci Adv2017 Apr 01; 3
AB  - 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.