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Cryo-EM structures and dynamics of substrate-engaged human 26S proteasome
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Abstract
The proteasome is an ATP-dependent, 2.5-megadalton molecular machine that is responsible for selective protein degradation in eukaryotic cells. Here we present cryo-electron microscopy structures of the substrate-engaged human proteasome in seven conformational states at 2.8-3.6 Å resolution, captured during breakdown of a polyubiquitylated protein. These structures illuminate a spatiotemporal continuum of dynamic substrate-proteasome interactions from ubiquitin recognition to substrate translocation, during which ATP hydrolysis sequentially navigates through all six ATPases. There are three principal modes of coordinated hydrolysis, featuring hydrolytic events in two oppositely positioned ATPases, in two adjacent ATPases and in one ATPase at a time. These hydrolytic modes regulate deubiquitylation, initiation of translocation and processive unfolding of substrates, respectively. Hydrolysis of ATP powers a hinge-like motion in each ATPase that regulates its substrate interaction. Synchronization of ATP binding, ADP release and ATP hydrolysis in three adjacent ATPases drives rigid-body rotations of substrate-bound ATPases that are propagated unidirectionally in the ATPase ring and unfold the substrate.
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“P320 in PSMC5 is located outside of the AAA ATPase domain (Fig. 3C) and at the interface of the 19S RP and the 20S CP [34] (Fig. 3D).”
From PSMC5 insufficiency and P320R mutation impair proteasome function (2024) · cites this paper as [34]
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Metadata
- Authors
- Dong, Y., Zhang, S., Wu, Z., Li, X., Wang, W. L., Zhu, Y., Stoilova-McPhie, S., Lu, Y., Finley, D., & Mao, Y.
- Affiliations
- Harvard University (US)
- Peking University (CN)
- Corresponding author
- Mao, Youdong
- ORCID
- Venue
- Nature
- Published
- 2018-11-12
- Volume
- 565
- Issue
- 7737
- Pages
- 49-55
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6370054
- OpenAlex
- W2900290772
- Cited by
- 328
- References
- 77
- Citations by year
- 2026: 27 · 2025: 47 · 2024: 30 · 2023: 36 · 2022: 44 · 2021: 46 · 2020: 49 · 2019: 48
- FWCI
- 12.90
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Science Foundation (1541959)
- Harvard University (1541959)
- National Natural Science Foundation of China (11774012, 91530321)
- Peking University
- Recruitment Program of Global Experts
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM043601, R37GM043601)
- National Institute of Allergy and Infectious Diseases (UM1AI100645)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- 26S proteasome, ATP hydrolysis, substrate translocation, deubiquitination, ubiquitin recognition, protein unfolding
- MeSH terms
- Adenosine Triphosphatases, Adenosine Triphosphate, Allosteric Regulation, Humans, Hydrolysis, Models, Molecular, Protein Conformation, Substrate Specificity, Holoenzymes, Cryoelectron Microscopy, Protein Structure, Quaternary, Proteasome Endopeptidase Complex, Ubiquitination, Protein Unfolding
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