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

Citation:

Tal Oppenheim, Radzinski, Meytal , Braitbard, Merav , Brielle, Esther S, Yogev, Ohad , Goldberger, Eliya , Yesharim, Yarden , Ravid, Tommer , Schneidman-Duhovny, Dina , and Reichmann, Dana . 2023. “The Cdc48 N-Terminal Domain Has A Molecular Switch That Mediates The Npl4-Ufd1-Cdc48 Complex Formation”. https://www.sciencedirect.com/science/article/pii/S0969212623001697.

Abstract:

SummaryCdc48 (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.