@article{f49c1fa5b192429982684741b03ae3a2,
title = "Ubp6 deubiquitinase controls conformational dynamics and substrate degradation of the 26S proteasome",
abstract = "Substrates are targeted for proteasomal degradation through the attachment of ubiquitin chains that need to be removed by proteasomal deubiquitinases before substrate processing. In budding yeast, the deubiquitinase Ubp6 trims ubiquitin chains and affects substrate processing by the proteasome, but the underlying mechanisms and the location of Ubp6 within the holoenzyme have been elusive. Here we show that Ubp6 activity strongly responds to interactions with the base ATPase and the conformational state of the proteasome. Electron microscopy analyses reveal that ubiquitin-bound Ubp6 contacts the N ring and AAA+ ring of the ATPase hexamer and is in proximity to the deubiquitinase Rpn11. Ubiquitin-bound Ubp6 inhibits substrate deubiquitination by Rpn11, stabilizes the substrate-engaged conformation of the proteasome and allosterically interferes with the engagement of a subsequent substrate. Ubp6 may thus act as a ubiquitin-dependent 'timer' to coordinate individual processing steps at the proteasome and modulate substrate degradation.",
author = "Charlene Bashore and Dambacher, {Corey M.} and Goodall, {Ellen A.} and Matyskiela, {Mary E.} and Lander, {Gabriel C.} and Andreas Martin",
note = "Funding Information: We thank the members of the Martin laboratory for helpful discussions, C. Padovani and R. Beckwith (both in A.M.{\textquoteright}s laboratory) for purified ubiquitin dimers and proteasome base subcomplexes, respectively. We are also grateful to T. Wandless (Stanford School of Medicine) for providing the lysineless GFP construct, K. Nyquist for cloning the GFP model substrate used in degradation assays and the D.O. Morgan laboratory (University of California, San Francisco) for ubiquitin reagents. C.B. acknowledges support from the US National Science Foundation Graduate Research Fellowship, and M.E.M. acknowledges support from the American Cancer Society (grant 121453-PF-11-178-01-TBE). This research was also funded in part by the Damon Runyon Cancer Research Foundation (DFS-#07-13), the Pew Scholars program, the Searle Scholars program and the US National Institutes of Health (grant DP2 EB020402-01) to G.C.L. A.M. acknowledges support from the Searle Scholars Program, start-up funds from the Molecular & Cell Biology Department at the University of California, Berkeley, the US National Institutes of Health (grant R01-GM094497) and the US National Science Foundation CAREER Program (NSF-MCB-1150288). Publisher Copyright: {\textcopyright} 2015 Nature America, Inc. All rights reserved.",
year = "2015",
month = sep,
day = "3",
doi = "10.1038/nsmb.3075",
language = "English (US)",
volume = "22",
pages = "712--719",
journal = "Nature Structural Biology",
issn = "1545-9993",
publisher = "Nature Publishing Group",
number = "9",
}