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


ABSTRACT: When in the closed form, the substrate translocation channel of the proteasome core particle (CP) is blocked by the convergent N termini of ?-subunits. To probe the role of channel gating in mammalian proteasomes, we deleted the N-terminal tail of ?3; the resulting ?3?N 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.

SUBMITTER: Choi WH 

PROVIDER: S-EPMC4786872 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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

Choi Won Hoon WH   de Poot Stefanie A H SA   Lee Jung Hoon JH   Kim Ji Hyeon JH   Han Dong Hoon DH   Kim Yun Kyung YK   Finley Daniel D   Lee Min Jae MJ  

Nature communications 20160309


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  ...[more]

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