The Cdc48 N-terminal domain has a molecular switch that mediates the Npl4-Ufd1-Cdc48 complex formation

Tal Oppenheim, Meytal Radzinski, Merav Braitbard, Esther S. Brielle, Ohad Yogev, Eliya Goldberger, Yarden Yesharim, Tommer Ravid, Dina Schneidman-Duhovny*, Dana Reichmann*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Cdc48 (VCP/p97) is a major AAA-ATPase involved in protein quality control, along with its canonical cofactors Ufd1 and Npl4 (UN). Here, we present novel structural insights into the interactions within the Cdc48-Npl4-Ufd1 ternary complex. Using integrative modeling, we combine subunit structures with crosslinking mass spectrometry (XL-MS) to map the interaction between Npl4 and Ufd1, alone and in complex with Cdc48. We describe the stabilization of the UN assembly upon binding with the N-terminal-domain (NTD) of Cdc48 and identify a highly conserved cysteine, C115, at the Cdc48-Npl4-binding interface which is central to the stability of the Cdc48-Npl4-Ufd1 complex. Mutation of Cys115 to serine disrupts the interaction between Cdc48-NTD and Npl4-Ufd1 and leads to a moderate decrease in cellular growth and protein quality control in yeast. Our results provide structural insight into the architecture of the Cdc48-Npl4-Ufd1 complex as well as its in vivo implications.

Original languageAmerican English
Pages (from-to)764-779.e8
Issue number7
StatePublished - 6 Jul 2023

Bibliographical note

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© 2023 Elsevier Ltd


  • CDC48
  • CL-MS
  • NPL4
  • UFD1
  • crosslinking coupled with MS (XL-MS)
  • integrative modeling
  • protein quality control
  • structural mass spectrometry


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