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The UBX domain in UBXD1 organizes ubiquitin binding at the C-terminus of the VCP/p97 AAA-ATPase

Author

Listed:
  • Mike Blueggel

    (University of Duisburg-Essen)

  • Alexander Kroening

    (University of Duisburg-Essen)

  • Matthias Kracht

    (University of Duisburg-Essen)

  • Johannes van den Boom

    (University of Duisburg-Essen)

  • Matthias Dabisch

    (University of Duisburg-Essen)

  • Anna Goehring

    (University of Duisburg-Essen)

  • Farnusch Kaschani

    (University of Duisburg-Essen)

  • Markus Kaiser

    (University of Duisburg-Essen)

  • Peter Bayer

    (University of Duisburg-Essen)

  • Hemmo Meyer

    (University of Duisburg-Essen)

  • Christine Beuck

    (University of Duisburg-Essen)

Abstract

The AAA+ ATPase p97/VCP together with different sets of substrate-delivery adapters and accessory cofactor proteins unfolds ubiquitinated substrates to facilitate degradation by the proteasome. The UBXD1 cofactor is connected to p97-associated multisystem proteinopathy but its biochemical function and structural organization on p97 has remained largely elusive. Using a combination of crosslinking mass spectrometry and biochemical assays, we identify an extended UBX (eUBX) module in UBXD1 related to a lariat in another cofactor, ASPL. Of note, the UBXD1-eUBX intramolecularly associates with the PUB domain in UBXD1 close to the substrate exit pore of p97. The UBXD1 PUB domain can also bind the proteasomal shuttling factor HR23b via its UBL domain. We further show that the eUBX domain has ubiquitin binding activity and that UBXD1 associates with an active p97-adapter complex during substrate unfolding. Our findings suggest that the UBXD1-eUBX module receives unfolded ubiquitinated substrates after they exit the p97 channel and before hand-over to the proteasome. The interplay of full-length UBXD1 and HR23b and their function in the context of an active p97:UBXD1 unfolding complex remains to be studied in future work.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38604-4
    DOI: 10.1038/s41467-023-38604-4
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    References listed on IDEAS

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    1. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
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    3. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
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