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  Crystal structure of the proteasomal deubiquitylation module Rpn8-Rpn11

Pathare, G. R., Nagy, I., Sledz, P., Anderson, D. J., Zhou, H.-J., Pardon, E., et al. (2014). Crystal structure of the proteasomal deubiquitylation module Rpn8-Rpn11. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 111(8), 2984-2989. doi:10.1073/pnas.1400546111.

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Pathare, Ganesh Ramnath1, Author           
Nagy, Istvan1, Author           
Sledz, Pawel1, Author           
Anderson, Daniel J.2, Author
Zhou, Han-Jie2, Author
Pardon, Els2, Author
Steyaert, Jan2, Author
Förster, Friedrich1, 3, Author           
Bracher, Andreas4, Author           
Baumeister, Wolfgang1, Author           
Affiliations:
1Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565142              
2external, ou_persistent22              
3Förster, Friedrich / Modeling of Protein Complexes, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565148              
4Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565152              

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Free keywords: INITIATION-FACTOR 3; 26S PROTEASOME; POLYUBIQUITIN CHAINS; REGULATORY PARTICLE; UBIQUITIN SYSTEM; COP9 SIGNALOSOME; AMSH-LP; DEGRADATION; SUBUNIT; ARCHITECTUREMpr1; POH1; PSMD7; PSMD14; JAMM protease;
 Abstract: The ATP-dependent degradation of polyubiquitylated proteins by the 26S proteasome is essential for the maintenance of proteome stability and the regulation of a plethora of cellular processes. Degradation of substrates is preceded by the removal of polyubiquitin moieties through the isopeptidase activity of the subunit Rpn11. Here we describe three crystal structures of the heterodimer of the Mpr1-Pad1-N-terminal domains of Rpn8 and Rpn11, crystallized as a fusion protein in complex with a nanobody. This fusion protein exhibits modest deubiquitylation activity toward a model substrate. Full activation requires incorporation of Rpn11 into the 26S proteasome and is dependent on ATP hydrolysis, suggesting that substrate processing and polyubiquitin removal are coupled. Based on our structures, we propose that premature activation is prevented by the combined effects of low intrinsic ubiquitin affinity, an insertion segment acting as a physical barrier across the substrate access channel, and a conformationally unstable catalytic loop in Rpn11. The docking of the structure into the proteasome EM density revealed contacts of Rpn11 with ATPase subunits, which likely stabilize the active conformation and boost the affinity for the proximal ubiquitin moiety. The narrow space around the Rpn11 active site at the entrance to the ATPase ring pore is likely to prevent erroneous deubiquitylation of folded proteins.

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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: 000332180900031
DOI: 10.1073/pnas.1400546111
 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 (8) Sequence Number: - Start / End Page: 2984 - 2989 Identifier: ISSN: 0027-8424