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

Mike Blueggel, Alexander Kroening, Matthias Kracht, Johannes van den Boom, Matthias Dabisch, Anna Goehring, Farnusch Kaschani, Markus Kaiser, Peter Bayer, Hemmo Meyer and Christine Beuck ()
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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

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38604-4

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