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PreprintCited by 33Ubiquitin and proteasome pathwaysHeat shock proteins researchEnzyme Structure and Function

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Visualizing chaperone-mediated multistep assembly of the human 20S proteasome

Open access
Adolf, Frank, Du, Jiale, Goodall, Ellen A., Walsh, Richard M., Rawson, Shaun, von Gronau, Susanne, Harper, J. Wade, Hanna, John, Schulman, Brenda A.·2024·Nature Structural & Molecular Biology
DOI 10.1101/2024.01.27.577538PMC PMC11327110

Preprint — published as 10.1038/s41594-024-01268-9 · Paper page

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Abstract

Dedicated assembly factors orchestrate stepwise production of many molecular machines, including the 28-subunit proteasome core particle (CP) that mediates protein degradation. Here, we report cryo-EM reconstructions of seven recombinant human subcomplexes that visualize all five chaperones and the three active site propeptides across a wide swath of the assembly pathway. Comparison of these chaperone-bound intermediates and a matching mature CP reveals molecular mechanisms determining the order of successive subunit additions, and how proteasome subcomplexes and assembly factors structurally adapt upon progressive subunit incorporation to stabilize intermediates, facilitate the formation of subsequent intermediates, and ultimately rearrange to coordinate proteolytic activation with gated access to active sites. The structural findings reported here explain many previous biochemical and genetic observations. This work establishes a methodologic approach for structural analysis of multiprotein complex assembly intermediates, illuminates specific functions of assembly factors, and reveals conceptual principles underlying human proteasome biogenesis.

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Metadata

Authors
Adolf, F., Du, J., Goodall, E. A., Walsh, R. M., Rawson, S., von Gronau, S., Harper, J. W., Hanna, J., & Schulman, B. A.
Affiliations
  • Max Planck Institute of Biochemistry (DE)
  • Harvard University (US)
  • Brigham and Women's Hospital (US)
Corresponding author
  • Adolf, Frank
  • Hanna, John
  • Schulman, Brenda A.
ORCID
Venue
Nature Structural & Molecular Biology
Publisher
openRxiv
Published
2024-01-28
Volume
31
Issue
8
Pages
1176-1188
ISSN
1545-9985 (ISSN-L)
DOI
10.1101/2024.01.27.577538
PMC
PMC11327110
OpenAlex
W4394691490
Cited by
33
References
1
Citations by year
2026: 14 · 2025: 15 · 2024: 4
FWCI
4.48
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Structural & Molecular Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • Aligning Science Across Parkinson’s
  • Deutsche Forschungsgemeinschaft (SCHU 3196/1‐1, SCHU 3196/1)
  • Max-Planck-Gesellschaft
  • Max-Planck-Institut für Bildungsforschung
  • National Institutes of Health (NS083524)
  • Leibniz-Gemeinschaft
  • National Institute on Aging (R01AG011085)
  • National Institute of General Medical Sciences (R01GM144367)
  • National Institute of Neurological Disorders and Stroke (R01NS083524)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
Keywords
20S proteasome, proteasome core particle, proteasome assembly, molecular chaperones, assembly intermediates, multiprotein complex assembly, assembly factors, proteolytic activation, protein degradation

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