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

Author

Listed:
  • Anup Arumughan

    (Max Delbrück Center for Molecular Medicine)

  • Yvette Roske

    (Max Delbrück Center for Molecular Medicine)

  • Carolin Barth

    (Max Delbrück Center for Molecular Medicine)

  • Laura Lleras Forero

    (Max Delbrück Center for Molecular Medicine)

  • Kenny Bravo-Rodriguez

    (Max-Planck-Institute for Coal Research)

  • Alexandra Redel

    (Max Delbrück Center for Molecular Medicine)

  • Simona Kostova

    (Max Delbrück Center for Molecular Medicine)

  • Erik McShane

    (Max Delbrück Center for Molecular Medicine)

  • Robert Opitz

    (Max Delbrück Center for Molecular Medicine)

  • Katja Faelber

    (Max Delbrück Center for Molecular Medicine)

  • Kirstin Rau

    (Max Delbrück Center for Molecular Medicine)

  • Thorsten Mielke

    (Max Planck Institute for Molecular Genetics)

  • Oliver Daumke

    (Max Delbrück Center for Molecular Medicine)

  • Matthias Selbach

    (Max Delbrück Center for Molecular Medicine)

  • Elsa Sanchez-Garcia

    (Max-Planck-Institute for Coal Research)

  • Oliver Rocks

    (Max Delbrück Center for Molecular Medicine)

  • Daniela Panáková

    (Max Delbrück Center for Molecular Medicine)

  • Udo Heinemann

    (Max Delbrück Center for Molecular Medicine
    Institute for Chemistry and Biochemistry, Freie Universität Berlin)

  • Erich E. Wanker

    (Max Delbrück Center for Molecular Medicine)

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.

Suggested Citation

  • Anup Arumughan & Yvette Roske & Carolin Barth & Laura Lleras Forero & Kenny Bravo-Rodriguez & Alexandra Redel & Simona Kostova & Erik McShane & Robert Opitz & Katja Faelber & Kirstin Rau & Thorsten Mi, 2016. "Quantitative interaction mapping reveals an extended UBX domain in ASPL that disrupts functional p97 hexamers," Nature Communications, Nature, vol. 7(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13047
    DOI: 10.1038/ncomms13047
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    Cited by:

    1. Mike Blueggel & Alexander Kroening & Matthias Kracht & Johannes van den Boom & Matthias Dabisch & Anna Goehring & Farnusch Kaschani & Markus Kaiser & Peter Bayer & Hemmo Meyer & Christine Beuck, 2023. "The UBX domain in UBXD1 organizes ubiquitin binding at the C-terminus of the VCP/p97 AAA-ATPase," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Amir Pozner & Li Li & Shiv Prakash Verma & Shuxin Wang & Jared J. Barrott & Mary L. Nelson & Jamie S. E. Yu & Gian Luca Negri & Shane Colborne & Christopher S. Hughes & Ju-Fen Zhu & Sydney L. Lambert , 2024. "ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97," Nature Communications, Nature, vol. 15(1), pages 1-21, December.

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