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  Quantitative interaction mapping reveals an extended UBX domain in ASPL that disrupts functional p97 hexamers

Arumughan, A., Roske, Y., Barth, C., Forero, L. L., Bravo-Rodriguez, K., Redel, A., et al. (2016). Quantitative interaction mapping reveals an extended UBX domain in ASPL that disrupts functional p97 hexamers. Nature Communications, 7: 13047/1-13. doi:10.1038/ncomms13047.

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 Creators:
Arumughan, Anup 1, Author
Roske, Yvette 1, Author
Barth, Carolin 1, Author
Forero, Laura Lleras1, Author
Bravo-Rodriguez, Kenny2, Author              
Redel, Alexandra 1, Author
Kostova, Simona 1, Author
McShane, Erik 1, Author
Robert Opitz, Robert 1, Author
Faelber, Katja 1, Author
Rau, Kirstin1, Author
Mielke, Thorsten 3, Author
Daumke, Oliver 1, Author
Selbach, Matthias 1, Author
Sanchez-Garcia, Elsa2, Author              
Rocks, Oliver 1, Author
Daniela Panáková, Daniela 1, Author
Heinemann, Udo1, 4, Author
Wanker, Erich E.1, Author
Affiliations:
1Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany, ou_persistent22              
2Research Group Sánchez-García, Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1950289              
3Max Planck Institute for Molecular Genetics, Ihnestraße 63-73, 14194 Berlin, Germany, ou_persistent22              
4Institute for Chemistry and Biochemistry, Freie Universität Berlin, Takustraße 6, 14195 Berlin, Germany, ou_persistent22              

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Free keywords: ER-associated degradation; Nucleotide-binding proteins; X-ray crystallography
 Abstract: Interaction mapping is a powerful strategy to elucidate the biological function of protein assemblies and their regulators. Here, we report the generation of a quantitative interaction network, directly linking 14 human proteins to the AAA+ ATPase p97, an essential hexameric protein with multiple cellular functions. We show that the high-affinity interacting protein ASPL efficiently promotes p97 hexamer disassembly, resulting in the formation of stable p97:ASPL heterotetramers. High-resolution structural and biochemical studies indicate that an extended UBX domain (eUBX) in ASPL is critical for p97 hexamer disassembly and facilitates the assembly of p97:ASPL heterotetramers. This spontaneous process is accompanied by a reorientation of the D2 ATPase domain in p97 and a loss of its activity. Finally, we demonstrate that overproduction of ASPL disrupts p97 hexamer function in ERAD and that engineered eUBX polypeptides can induce cell death, providing a rationale for developing anti-cancer polypeptide inhibitors that may target p97 activity.

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Language(s): eng - English
 Dates: 2016-02-162016-08-292016-10-20
 Publication Status: Published online
 Pages: 13
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/ncomms13047
 Degree: -

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Title: Nature Communications
  Abbreviation : Nat. Commun.
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 7 Sequence Number: 13047/1-13 Start / End Page: - Identifier: ISSN: 2041-1723
CoNE: https://pure.mpg.de/cone/journals/resource/2041-1723