The UBX domain in UBXD1 organizes ubiquitin binding at the C-terminus of the VCP/p97 AAA-ATPase.
Carrier Proteins
/ metabolism
ATPases Associated with Diverse Cellular Activities
/ metabolism
Adaptor Proteins, Signal Transducing
/ genetics
Proteasome Endopeptidase Complex
/ metabolism
Valosin Containing Protein
/ genetics
Adenosine Triphosphatases
/ metabolism
Autophagy-Related Proteins
/ genetics
Protein Structure, Tertiary
Protein Binding
Ubiquitin
/ metabolism
Cell Cycle Proteins
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
05 06 2023
05 06 2023
Historique:
received:
25
02
2022
accepted:
09
05
2023
medline:
7
6
2023
pubmed:
6
6
2023
entrez:
5
6
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37277335
doi: 10.1038/s41467-023-38604-4
pii: 10.1038/s41467-023-38604-4
pmc: PMC10241913
doi:
Substances chimiques
Carrier Proteins
0
ATPases Associated with Diverse Cellular Activities
EC 3.6.4.-
Adaptor Proteins, Signal Transducing
0
Proteasome Endopeptidase Complex
EC 3.4.25.1
Valosin Containing Protein
EC 3.6.4.6
Adenosine Triphosphatases
EC 3.6.1.-
Autophagy-Related Proteins
0
Ubiquitin
0
Cell Cycle Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3258Informations de copyright
© 2023. The Author(s).
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