Structural insights of the p97/VCP AAA+ ATPase: How adapter interactions coordinate diverse cellular functionality

Area of Science:

• Biochemistry
• Molecular Biology
• Cell Biology

Background:

• Valosin-containing protein (p97) is a crucial eukaryotic AAA+ ATPase involved in protein homeostasis, membrane remodeling, and chromatin regulation.
• Dysregulation of p97 is linked to neurodegenerative diseases and cancer, identifying it as a key therapeutic target.
• p97 functions by extracting polypeptide substrates from macromolecular assemblies via ATP hydrolysis-driven translocation.

Purpose of the Study:

• To review the known functions of p97 adapter proteins.
• To highlight recent structural and biochemical advances in understanding adapter-mediated p97 regulation.
• To underscore the therapeutic potential of targeting p97-adapter interactions.

Main Methods:

• Literature review of existing studies on p97 and its adapters.
• Analysis of recent structural and biochemical data.
• Synthesis of current knowledge on p97-adapter mechanisms.

Main Results:

• Over 30 adapter proteins modulate p97 activity, enabling diverse functions like protein extraction from organelles.
• Adapters facilitate p97 substrate recruitment and modification, explaining p97's functional versatility.
• Recent structural and biochemical studies reveal diverse mechanisms of adapter-mediated p97 regulation.

Conclusions:

• p97 adapter proteins are critical regulators of its diverse cellular functions.
• The mechanisms of p97 regulation by adapters are complex and not fully understood.
• Further exploration of p97-adapter interactions offers significant therapeutic opportunities for p97-associated diseases.