Seesaw conformations of Npl4 in the human p97 complex and the inhibitory mechanism of a disulfiram derivative

Man Pan, Qingyun Zheng, Yuanyuan Yu, Huasong Ai, Yuan Xie, Xin Zeng, Chu Wang, Lei Liu () and Minglei Zhao ()
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Man Pan: The University of Chicago
Qingyun Zheng: Tsinghua University
Yuanyuan Yu: The University of Chicago
Huasong Ai: Tsinghua University
Yuan Xie: The University of Chicago
Xin Zeng: Peking University
Chu Wang: Peking University
Lei Liu: Tsinghua University
Minglei Zhao: The University of Chicago

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract p97, also known as valosin-containing protein (VCP) or Cdc48, plays a central role in cellular protein homeostasis. Human p97 mutations are associated with several neurodegenerative diseases. Targeting p97 and its cofactors is a strategy for cancer drug development. Despite significant structural insights into the fungal homolog Cdc48, little is known about how human p97 interacts with its cofactors. Recently, the anti-alcohol abuse drug disulfiram was found to target cancer through Npl4, a cofactor of p97, but the molecular mechanism remains elusive. Here, using single-particle cryo-electron microscopy (cryo-EM), we uncovered three Npl4 conformational states in complex with human p97 before ATP hydrolysis. The motion of Npl4 results from its zinc finger motifs interacting with the N domain of p97, which is essential for the unfolding activity of p97. In vitro and cell-based assays showed that the disulfiram derivative bis-(diethyldithiocarbamate)-copper (CuET) can bypass the copper transporter system and inhibit the function of p97 in the cytoplasm by releasing cupric ions under oxidative conditions, which disrupt the zinc finger motifs of Npl4, locking the essential conformational switch of the complex.

Date: 2021
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DOI: 10.1038/s41467-020-20359-x

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