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Molecular Mechanisms Driving and Regulating the AAA+ ATPase VCP/p97, an Important Therapeutic Target for Treating

Sepideh Valimehr1,2,3,4, Ashish Sethi1,2,5, Manjari Shukla6

  • 1Department of Biochemistry & Pharmacology, The University of Melbourne, Melbourne, VIC 3010, Australia.

Biomolecules
|May 27, 2023
PubMed

Insights

The AAA+ ATPase p97/VCP is crucial for cellular functions and virus replication, making it a key target for cancer and neurodegenerative disease therapies. Understanding its mechanism aids in developing targeted inhibitors.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • p97/VCP is a highly conserved type II AAA+ ATPase involved in numerous cellular processes.
  • It functions as a mechanochemical enzyme, utilizing ATP binding and hydrolysis to generate force for protein unfolding and other tasks.
  • p97's diverse functions are mediated by interactions with numerous cofactors and adaptors.

Purpose of the Study:

  • To review the current understanding of the molecular mechanism of p97/VCP during its ATPase cycle.
  • To elucidate the regulation of p97/VCP by its cofactors and small-molecule inhibitors.
  • To explore how pathogenic mutations affect p97/VCP's conformational changes and ATPase cycle.

Main Methods:

  • Comparative analysis of structural data across different nucleotide states.
  • Examination of p97/VCP in the presence and absence of substrates and inhibitors.
  • Review of existing literature on p97/VCP structure, function, and regulation.

Main Results:

  • Detailed structural insights into the ATPase cycle of p97/VCP.
  • Understanding of how cofactors and inhibitors modulate p97/VCP activity.
  • Characterization of conformational changes induced by gain-of-function mutations.

Conclusions:

  • Mechanistic knowledge of p97/VCP is essential for designing targeted modulators and inhibitors.
  • p97/VCP's role in disease necessitates further investigation into its regulatory mechanisms.
  • Structural and mechanistic insights pave the way for developing novel therapeutic strategies.
Keywords:
ATPasecryo-electron microscopyp97-VCP

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