Structural and functional deviations in disease-associated p97 mutants.

Area of Science:

• Biochemistry
• Molecular Biology
• Cell Biology

Background:

• The AAA protein p97 plays crucial roles in various cellular functions.
• Missense mutations at the interface of p97's functional domains cause human disorders, including inclusion body myopathy associated with Paget's disease of the bone and frontotemporal dementia (IBMPFD).
• Previous research has characterized IBMPFD mutants at cellular and molecular levels, revealing their involvement in cellular pathways.

Purpose of the Study:

• To investigate the molecular mechanisms underlying p97 dysfunction in IBMPFD.
• To elucidate how missense mutations affect p97's enzymatic activity, protein binding, and conformational dynamics.

Main Methods:

• Biochemical and biophysical characterization of pathogenic p97 mutants.
• Structural studies using techniques like X-ray crystallography.
• Analysis of nucleotide binding properties and conformational changes.

Main Results:

• Pathogenic p97 mutants exhibit altered nucleotide binding in the D1-domains.
• Mutant p97 undergoes a uniform N-domain conformational transition (Down- to Up-conformation) with ATPγS, unlike wild-type p97.
• Alterations in p97's binding to adaptor proteins were observed for some partners.

Conclusions:

• Missense mutations in p97 disrupt its enzymatic activity and intracellular functions, leading to IBMPFD.
• Structural and biochemical analyses provide new insights into the pathogenic mechanisms of p97 mutations.
• Understanding these mechanisms can inform therapeutic strategies for IBMPFD.