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  Molecular Details Underlying Dynamic Structures and Regulation of the Human 26S Proteasome

Wang, X., Cimermancic, P., Yu, C., Schweitzer, A., Chopra, N., Engel, J. L., et al. (2017). Molecular Details Underlying Dynamic Structures and Regulation of the Human 26S Proteasome. Molecular and Cellular Proteomics, 16(5), 840-854. doi:10.1074/mcp.M116.065326.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-E22B-1 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-E22C-0
Genre: Journal Article

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 Creators:
Wang, Xiaorong1, Author
Cimermancic, Peter1, Author
Yu, Clinton1, Author
Schweitzer, Andreas2, Author              
Chopra, Nikita1, Author
Engel, James L.1, Author
Greenberg, Charles1, Author
Huszagh, Alexander S.1, Author
Beck, Florian2, Author              
Sakata, Eri2, Author              
Yang, Yingying1, Author
Novitsky, Eric J.1, Author
Leitner, Alexander1, Author
Nanni, Paolo1, Author
Kahraman, Abdullah1, Author
Guo, Xing1, Author
Dixon, Jack E.1, Author
Rychnovsky, Scott D.1, Author
Aebersold, Ruedi1, Author
Baumeister, Wolfgang2, Author              
Sali, Andrej1, AuthorHuang, Lan1, Author more..
Affiliations:
1external, ou_persistent22              
2Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565142              

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Free keywords: PROTEIN-PROTEIN INTERACTIONS; STARVATION-INDUCED AUTOPHAGY; LINKING MASS-SPECTROMETRY; CHEMICAL CROSS-LINKING; AFFINITY PURIFICATION; UBIQUITIN RECEPTORS; INTERACTION NETWORK; CRYSTAL-STRUCTURE; LINKED PEPTIDES; 20S PROTEASOMEBiochemistry & Molecular Biology;
 Abstract: The 26S proteasome is the macromolecular machine responsible for ATP/ubiquitin dependent degradation. As aberration in proteasomal degradation has been implicated in many human diseases, structural analysis of the human 26S proteasome complex is essential to advance our understanding of its action and regulation mechanisms. In recent years, cross-linking mass spectrometry (XL-MS) has emerged as a powerful tool for elucidating structural topologies of large protein assemblies, with its unique capability of studying protein complexes in cells. To facilitate the identification of cross-linked peptides, we have previously developed a robust amine reactive sulfoxide-containing MS-cleavable cross-linker, disuccinimidyl sulfoxide (DSSO). To better understand the structure and regulation of the human 26S proteasome, we have established new DSSO-based in vivo and in vitro XL-MS workflows by coupling with HB-tag based affinity purification to comprehensively examine protein-protein interactions within the 26S proteasome. In total, we have identified 447 unique lysine-to-lysine linkages delineating 67 interprotein and 26 intraprotein interactions, representing the largest cross-link dataset for proteasome complexes. In combination with EM maps and computational modeling, the architecture of the 26S proteasome was determined to infer its structural dynamics. In particular, three proteasome subunits Rpn1, Rpn6, and Rpt6 displayed multiple conformations that have not been previously reported. Additionally, cross-links between proteasome subunits and 15 proteasome interacting proteins including 9 known and 6 novel ones have been determined to demonstrate their physical interactions at the amino acid level. Our results have provided new insights on the dynamics of the 26S human proteasome and the methodologies presented here can be applied to study other protein complexes.

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Language(s): eng - English
 Dates: 2017
 Publication Status: Published in print
 Pages: 15
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: ISI: 000400759600011
DOI: 10.1074/mcp.M116.065326
 Degree: -

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Title: Molecular and Cellular Proteomics
Source Genre: Journal
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Publ. Info: Bethesda, MD : American Society for Biochemistry and Molecular Biology
Pages: - Volume / Issue: 16 (5) Sequence Number: - Start / End Page: 840 - 854 Identifier: ISSN: 1535-9476
CoNE: /journals/resource/111035577487002