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  Deep classification of a large cryo-EM dataset defines the conformational landscape of the 26S proteasome

Unverdorben, P., Beck, F., Sledz, P., Schweitzer, A., Pfeifer, G., Plitzko, J. M., et al. (2014). Deep classification of a large cryo-EM dataset defines the conformational landscape of the 26S proteasome. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 111(15), 5544-5549. doi:10.1073/pnas.1403409111.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0019-8CF0-0 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0019-8CF1-E
Genre: Journal Article

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 Creators:
Unverdorben, Pia1, Author              
Beck, Florian1, Author              
Sledz, Pawel1, Author              
Schweitzer, Andreas1, Author              
Pfeifer, Günter1, Author              
Plitzko, Jürgen M.1, Author              
Baumeister, Wolfgang1, Author              
Förster, Friedrich1, 2, Author              
Affiliations:
1Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565142              
2Förster, Friedrich / Modeling of Protein Complexes, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565148              

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Free keywords: ATP-FUELED MACHINES; REGULATORY PARTICLE; MOLECULAR ARCHITECTURE; CRYSTAL-STRUCTURE; 20S PROTEASOME; S PROTEASOME; RESOLUTION; TRANSLOCATION; DEGRADATION; INSIGHTSconformational switching; proteolysis; proteostasis; quality control;
 Abstract: The 26S proteasome is a 2.5 MDa molecular machine that executes the degradation of substrates of the ubiquitin-proteasome pathway. The molecular architecture of the 26S proteasome was recently established by cryo-EM approaches. For a detailed understanding of the sequence of events from the initial binding of polyubiquitylated substrates to the translocation into the proteolytic core complex, it is necessary to move beyond static structures and characterize the conformational landscape of the 26S proteasome. To this end we have subjected a large cryo-EM dataset acquired in the presence of ATP and ATP-gamma S to a deep classification procedure, which deconvolutes coexisting conformational states. Highly variable regions, such as the density assigned to the largest subunit, Rpn1, are now well resolved and rendered interpretable. Our analysis reveals the existence of three major conformations: in addition to the previously described ATP-hydrolyzing (ATP(h)) and ATP-gamma S conformations, an intermediate state has been found. Its AAA-ATPase module adopts essentially the same topology that is observed in the ATP(h) conformation, whereas the lid is more similar to the ATP-gamma S bound state. Based on the conformational ensemble of the 26S proteasome in solution, we propose a mechanistic model for substrate recognition, commitment, deubiquitylation, and translocation into the core particle.

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Language(s): eng - English
 Dates: 2014
 Publication Status: Published in print
 Pages: 6
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000334288600036
DOI: 10.1073/pnas.1403409111
 Degree: -

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Title: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Source Genre: Journal
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Publ. Info: 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA : NATL ACAD SCIENCES
Pages: - Volume / Issue: 111 (15) Sequence Number: - Start / End Page: 5544 - 5549 Identifier: ISSN: 0027-8424