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<p>The p97-UFD1L-NPLOC4 ATPase unfolds numerous proteins for proteasomal degradation, but whether it suffices to pull proteins out of lipid bilayer remains unclear. Here, we identify a conserved ubiquitin-binding helix (UBH) in many UBX-containing p97 adapters, including FAF2, across yeast, plants, and metazoans. The UBH-UBX substantially facilitates the engagement of ubiquitinated substrates with p97-UFD1L-NPLOC4, and enhances p97 motor’s working ATPase and unfolding activities by approximately twofold. Using purified p97-UFD1L-NPLOC4-FAF2<sup>UBH-UBX</sup>, we reconstitute membrane protein extraction from the ER and mitochondria, establishing p97-UFD1L-NPLOC4-FAF2 (p97-UNF) as a power-enhanced unfoldase. Deleting UBH or disrupting UBH-ubiquitin interaction impairs substrate targeting, reduces p97-UNF’s working ATPase and unfolding activities, and abolishes membrane protein extraction and degradation. We propose that UBH-UBX module amplifies p97’s mechanical output power, enabling the removal of challenging substrates from large assemblies and ensuring rapid responses to protein misfolding or regulatory signals in diverse physiological processes.</p>

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A UBH-UBX module amplifies p97/VCP’s unfolding power to facilitate protein extraction and degradation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月19日

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  • Xin-Yu Huo,
  • Di Liu,
  • Rong Zou,
  • Zhao-Peng Li,
  • Yunxia Li,
  • Lifeng Pan,
  • Yaoyang Zhang,
  • Zai-Rong Zhang

摘要

The p97-UFD1L-NPLOC4 ATPase unfolds numerous proteins for proteasomal degradation, but whether it suffices to pull proteins out of lipid bilayer remains unclear. Here, we identify a conserved ubiquitin-binding helix (UBH) in many UBX-containing p97 adapters, including FAF2, across yeast, plants, and metazoans. The UBH-UBX substantially facilitates the engagement of ubiquitinated substrates with p97-UFD1L-NPLOC4, and enhances p97 motor’s working ATPase and unfolding activities by approximately twofold. Using purified p97-UFD1L-NPLOC4-FAF2UBH-UBX, we reconstitute membrane protein extraction from the ER and mitochondria, establishing p97-UFD1L-NPLOC4-FAF2 (p97-UNF) as a power-enhanced unfoldase. Deleting UBH or disrupting UBH-ubiquitin interaction impairs substrate targeting, reduces p97-UNF’s working ATPase and unfolding activities, and abolishes membrane protein extraction and degradation. We propose that UBH-UBX module amplifies p97’s mechanical output power, enabling the removal of challenging substrates from large assemblies and ensuring rapid responses to protein misfolding or regulatory signals in diverse physiological processes.