Open-gate mutants of the mammalian proteasome show enhanced ubiquitin-conjugate degradation

Won Hoon Choi, Stefanie A. H. de Poot, Jung Hoon Lee, Ji Hyeon Kim, Dong Hoon Han, Yun Kyung Kim, Daniel Finley () and Min Jae Lee ()
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Won Hoon Choi: Seoul National University Graduate School
Stefanie A. H. de Poot: Harvard Medical School
Jung Hoon Lee: Seoul National University College of Medicine
Ji Hyeon Kim: Seoul National University Graduate School
Dong Hoon Han: Seoul National University College of Medicine
Yun Kyung Kim: Center for Neuro-Medicine, Korea Institute of Science and Technology (KIST)
Daniel Finley: Harvard Medical School
Min Jae Lee: Seoul National University Graduate School

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract When in the closed form, the substrate translocation channel of the proteasome core particle (CP) is blocked by the convergent N termini of α-subunits. To probe the role of channel gating in mammalian proteasomes, we deleted the N-terminal tail of α3; the resulting α3ΔN proteasomes are intact but hyperactive in the hydrolysis of fluorogenic peptide substrates and the degradation of polyubiquitinated proteins. Cells expressing the hyperactive proteasomes show markedly elevated degradation of many established proteasome substrates and resistance to oxidative stress. Multiplexed quantitative proteomics revealed ∼200 proteins with reduced levels in the mutant cells. Potentially toxic proteins such as tau exhibit reduced accumulation and aggregate formation. These data demonstrate that the CP gate is a key negative regulator of proteasome function in mammals, and that opening the CP gate may be an effective strategy to increase proteasome activity and reduce levels of toxic proteins in cells.

Date: 2016
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DOI: 10.1038/ncomms10963

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