VCF1 is a p97/VCP cofactor promoting recognition of ubiquitylated p97-UFD1-NPL4 substrates.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
19 Mar 2024
19 Mar 2024
Historique:
received:
20
07
2023
accepted:
07
03
2024
medline:
20
3
2024
pubmed:
20
3
2024
entrez:
20
3
2024
Statut:
epublish
Résumé
The hexameric AAA+ ATPase p97/VCP functions as an essential mediator of ubiquitin-dependent cellular processes, extracting ubiquitylated proteins from macromolecular complexes or membranes by catalyzing their unfolding. p97 is directed to ubiquitylated client proteins via multiple cofactors, most of which interact with the p97 N-domain. Here, we discover that FAM104A, a protein of unknown function also named VCF1 (VCP/p97 nuclear Cofactor Family member 1), acts as a p97 cofactor in human cells. Detailed structure-function studies reveal that VCF1 directly binds p97 via a conserved α-helical motif that recognizes the p97 N-domain with unusually high affinity, exceeding that of other cofactors. We show that VCF1 engages in joint p97 complex formation with the heterodimeric primary p97 cofactor UFD1-NPL4 and promotes p97-UFD1-NPL4-dependent proteasomal degradation of ubiquitylated substrates in cells. Mechanistically, VCF1 indirectly stimulates UFD1-NPL4 interactions with ubiquitin conjugates via its binding to p97 but has no intrinsic affinity for ubiquitin. Collectively, our findings establish VCF1 as an unconventional p97 cofactor that promotes p97-dependent protein turnover by facilitating p97-UFD1-NPL4 recruitment to ubiquitylated targets.
Identifiants
pubmed: 38503733
doi: 10.1038/s41467-024-46760-4
pii: 10.1038/s41467-024-46760-4
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2459Subventions
Organisme : Novo Nordisk Fonden (Novo Nordisk Foundation)
ID : NNF14CC0001
Organisme : Novo Nordisk Fonden (Novo Nordisk Foundation)
ID : NNF18OC0030752
Organisme : Lundbeckfonden (Lundbeck Foundation)
ID : R223-2016-281
Organisme : Det Frie Forskningsråd (Danish Council for Independent Research)
ID : 0134-00048B
Organisme : Danmarks Grundforskningsfond (Danish National Research Foundation)
ID : DNRF-115
Organisme : EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)
ID : 812829 (aDDRess)
Organisme : European Molecular Biology Organization (EMBO)
ID : ALTF 1149-2020
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 424228829
Organisme : EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
ID : 715975
Informations de copyright
© 2024. The Author(s).
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