Choi, Won Hoon de Poot, Stefanie A. H. Lee, Jung Hoon Kim, Ji Hyeon Han, Dong Hoon Kim, Yun Kyung Finley, Daniel Lee, Min Jae 2024-01-20T04:34:45Z 2024-01-20T04:34:45Z 2021-09-05 2016-03 2041-1723 https://pubs.kist.re.kr/handle/201004/124335 When in the closed form, the substrate translocation channel of the proteasome core particle (CP) is blocked by the convergent N termini of alpha-subunits. To probe the role of channel gating in mammalian proteasomes, we deleted the N-terminal tail of alpha 3; the resulting alpha 3 Delta 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 similar to 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. English NATURE PUBLISHING GROUP LARGE GENE LISTS 26S PROTEASOME PROTEIN-DEGRADATION ALZHEIMERS-DISEASE MASS-SPECTROMETRY ATP BINDING QUANTITATIVE PROTEOMICS TAU-AGGREGATION STRESS-RESPONSE 20S PROTEASOME Open-gate mutants of the mammalian proteasome show enhanced ubiquitin-conjugate degradation Article 10.1038/ncomms10963 1 NATURE COMMUNICATIONS, v.7 NATURE COMMUNICATIONS 7 scie scopus 000371730600001 2-s2.0-84960517495 Multidisciplinary Sciences Science & Technology - Other Topics Article LARGE GENE LISTS 26S PROTEASOME PROTEIN-DEGRADATION ALZHEIMERS-DISEASE MASS-SPECTROMETRY ATP BINDING QUANTITATIVE PROTEOMICS TAU-AGGREGATION STRESS-RESPONSE 20S PROTEASOME 타우 프로테오좀