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Quantitative interaction mapping reveals an extended UBX domain in ASPL that disrupts functional p97 hexamers
Arumughan, Anup ;  Roske, Yvette ;  Barth, Carolin ;  Forero, Laura Lleras ;  Bravo-Rodriguez, Kenny ;  Redel, Alexandra ;  Kostova, Simona ;  McShane, Erik ;  Opitz, Robert ;  Faelber, Katja ;  Rau, Kirstin ;  Mielke, Thorsten ;  Daumke, Oliver ;  Selbach, Matthias ;  Sanchez-Garcia, Elsa ;  Rocks, Oliver ;  Panakova, Daniela ;  Heinemann, Udo ;  Wanker, Erich E.

HaupttitelQuantitative interaction mapping reveals an extended UBX domain in ASPL that disrupts functional p97 hexamers
AutorArumughan, Anup
AutorRoske, Yvette
AutorBarth, Carolin
AutorForero, Laura Lleras
AutorBravo-Rodriguez, Kenny
AutorRedel, Alexandra
AutorKostova, Simona
AutorMcShane, Erik
AutorOpitz, Robert
AutorFaelber, Katja
AutorRau, Kirstin
AutorMielke, Thorsten
AutorDaumke, Oliver
AutorSelbach, Matthias
AutorSanchez-Garcia, Elsa
AutorRocks, Oliver
AutorPanakova, Daniela
AutorHeinemann, Udo
AutorWanker, Erich E.
Seitenzahl13 S.
Freie SchlagwörterER-associated degradation; Nucleotide-binding proteins; X-ray crystallography
DDC610 Medizin und Gesundheit
Auch erschienen inNature Communications. - 7 (2016), Artikel Nr. 13047
ZusammenfassungInteraction 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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Fachbereich/EinrichtungMedizinische Fakultät Charité - Universitätsmedizin Berlin
Erscheinungsjahr2016
Dokumententyp/-SammlungenWissenschaftlicher Artikel
SpracheEnglisch
RechteCreative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Anmerkungen des AutorsDer Artikel wurde in einer reinen Open-Access-Zeitschrift publiziert.
Erstellt am11.11.2016 - 11:59:03
Letzte Änderung11.11.2016 - 12:07:00
 
Statische URLhttp://edocs.fu-berlin.de/docs/receive/FUDOCS_document_000000025696
DOI10.1038/ncomms13047
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