The 20S as a stand-alone proteasome in cells can degrade the ubiquitin tag

The proteasome, the primary protease for ubiquitin-dependent proteolysis in eukaryotes, is usually found as a mixture of 30S, 26S, and 20S complexes. These complexes have common catalytic sites, which makes it challenging to determine their distinctive roles in intracellular proteolysis. Here, we ch...

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Bibliographic Details
Published in:	Nature communications Vol. 12; no. 1; p. 6173
Main Authors:	Sahu, Indrajit, Mali, Sachitanand M., Sulkshane, Prasad, Xu, Cong, Rozenberg, Andrey, Morag, Roni, Sahoo, Manisha Priyadarsini, Singh, Sumeet K., Ding, Zhanyu, Wang, Yifan, Day, Sharleen, Cong, Yao, Kleifeld, Oded, Brik, Ashraf, Glickman, Michael H.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 26-10-2021 Nature Publishing Group Nature Portfolio
Subjects:	101/28 13/1 13/106 38/109 38/88 38/90 631/45/474/2085 631/45/612/1254 631/535/1258/1259 631/80/474/582 82/16 82/29 82/58 82/80 82/83 Active sites Cell Hypoxia Cell Survival Degradation Eukaryotes Heart Failure - metabolism Heart Failure - pathology Humanities and Social Sciences Humans Hypoxia multidisciplinary Peptides Peptides - chemistry Peptides - metabolism Proteasome 26S Proteasome Endopeptidase Complex - chemistry Proteasome Endopeptidase Complex - metabolism Proteasomes Protein Conformation Proteins Proteolysis Science Science (multidisciplinary) Structure-function relationships Substrate Specificity Substrates Ubiquitin Ubiquitin - chemistry Ubiquitin - metabolism Ubiquitinated Proteins - chemistry Ubiquitinated Proteins - metabolism Ubiquitination
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Summary:	The proteasome, the primary protease for ubiquitin-dependent proteolysis in eukaryotes, is usually found as a mixture of 30S, 26S, and 20S complexes. These complexes have common catalytic sites, which makes it challenging to determine their distinctive roles in intracellular proteolysis. Here, we chemically synthesize a panel of homogenous ubiquitinated proteins, and use them to compare 20S and 26S proteasomes with respect to substrate selection and peptide-product generation. We show that 20S proteasomes can degrade the ubiquitin tag along with the conjugated substrate. Ubiquitin remnants on branched peptide products identified by LC-MS/MS, and flexibility in the 20S gate observed by cryo-EM, reflect the ability of the 20S proteasome to proteolyze an isopeptide-linked ubiquitin-conjugate. Peptidomics identifies proteasome-trapped ubiquitin-derived peptides and peptides of potential 20S substrates in Hi20S cells, hypoxic cells, and human failing-heart. Moreover, elevated levels of 20S proteasomes appear to contribute to cell survival under stress associated with damaged proteins. The 20S particle is part of the 26S proteasome, but also exists as a free complex. Here, the authors outline signature activities of the 20S and combine chemical, structural, functional and proteomic assays to show that the 20S can degrade ubiquitin tags along with conjugated substrates.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-021-26427-0