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Translocation of polyubiquitinated protein substrates by the hexameric Cdc48 ATPase

Zhejian Ji1, Hao Li1, Daniele Peterle2

  • 1Howard Hughes Medical Institute and Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.

Molecular Cell
|December 24, 2021
PubMed

Insights

The Cdc48 ATPase complex, with Ufd1/Npl4, extracts polyubiquitinated proteins by unfolding ubiquitin chains. This mechanism allows translocation and degradation of substrates, releasing unfolded proteins from the complex.

Area of Science:

  • Molecular Biology
  • Protein Degradation

Background:

  • The Cdc48 ATPase (p97/VCP) and its cofactor Ufd1/Npl4 are crucial for protein degradation.
  • This complex extracts ubiquitinated proteins from cellular structures for proteasomal processing.

Purpose of the Study:

  • To elucidate the mechanism by which the Cdc48 complex unfolds substrates.
  • To understand how Cdc48 translocates polypeptides, especially those with branched ubiquitin chains.

Main Methods:

  • Biochemical assays to study protein-protein interactions.
  • In vitro analysis of substrate unfolding and translocation by Cdc48.

Main Results:

  • Cdc48 primarily recognizes polyubiquitin chains, not the substrate protein directly.
  • Cooperative binding of Cdc48-Ufd1/Npl4 to ubiquitin initiates unfolding.
  • The complex translocates and unfolds polyubiquitinated substrates, including branched chains, facilitating their release.

Conclusions:

  • Cdc48-Ufd1/Npl4 employs a mechanical unfolding and translocation mechanism targeting polyubiquitin chains.
  • This process enables the extraction and subsequent degradation of diverse protein substrates.
Keywords:
AAA ATPaseNpl4Ufd1VCPp97translocationubiquitinunfolding

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