Imbalances in p97 co-factor interactions in human proteinopathy

Area of Science:

• Molecular biology
• Cellular biology
• Neuroscience

Background:

• The ubiquitin-selective chaperone p97 (also known as VCP) plays a critical role in cellular protein degradation pathways.
• Mutations in p97 are causative for the human disorder inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD).
• The precise molecular mechanisms underlying protein aggregation and degradation defects in IBMPFD remain unclear.

Purpose of the Study:

• To investigate the molecular basis of IBMPFD by examining the function of mutant p97 proteins.
• To identify common defects in IBMPFD-associated p97 mutations.
• To elucidate the role of p97 co-factor interactions in the pathogenesis of IBMPFD.

Main Methods:

• Analysis of IBMPFD-causing mutant p97 proteins.
• Conformational analysis of the p97 N domain.
• Co-immunoprecipitation assays to assess co-factor binding affinity.
• Comparison of mutant p97 binding profiles with known disease-associated interactions.

Main Results:

• IBMPFD-causing mutations in p97 induce conformational changes in its N domain, the primary site for regulatory co-factor binding.
• Mutant p97 proteins display significantly altered interactions with key co-factors.
• Specifically, binding of the ubiquitin ligase E4B is reduced, while binding of ataxin 3 is enhanced in IBMPFD mutants.
• These altered binding patterns mirror observations in other p97-related proteinopathies, such as spinocerebellar ataxia type 3.

Conclusions:

• Perturbed co-factor binding represents a common molecular defect in IBMPFD-associated p97 mutations.
• Imbalanced interactions between p97 and its co-factors are a critical pathological feature driving IBMPFD.
• These findings suggest that aberrant p97 co-factor dynamics may contribute to the pathogenesis of various proteinopathies involving p97.