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Structural and Functional Analysis of Disease-Linked p97 ATPase Mutant Complexes
Purbasha Nandi1, Shan Li2, Rod Carlo A Columbres2
1Biodesign Center for Applied Structural Discovery, School of Molecular Sciences, Arizona State University, Tempe, AZ 85287, USA.
International Journal of Molecular Sciences
|August 7, 2021
Summary
A mutation in the p97 ATPase causes IBMPFD/ALS by altering its structure and function. This study reveals how the p97R155H mutation and p47 cofactor interaction lead to ATPase dysregulation in this genetic disorder.
Area of Science:
- Biochemistry
- Structural Biology
- Genetics
Background:
- IBMPFD/ALS is a genetic disorder linked to p97 ATPase mutations.
- The precise mechanisms of p97 ATPase malfunction in disease remain elusive.
Purpose of the Study:
- To elucidate how the p97R155H mutation affects p97 ATPase regulation and cofactor interaction.
- To visualize the structural dynamics of p97R155H with its p47 cofactor.
Main Methods:
- Single-particle cryo-electron microscopy (cryo-EM) to determine structures.
- Functional assays to assess ATPase activity.
- Analysis of protein-nucleotide interactions.
Main Results:
- The p97R155H mutant exists as a dodecamer, dissociating into hexamers upon nucleotide binding.
- N-domains of p97R155H adopt distinct conformations in different nucleotide-bound states.
- p47 binding influences p97R155H ATPase activity by altering arginine finger conformations.
Conclusions:
- The p97R155H mutation leads to ATPase dysregulation through altered protein structure and cofactor interactions.
- Miscommunication between functional modules of p97R155H contributes to the disease mechanism.
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