Abstract
IBMPFD/ALS is a genetic disorder caused by a single amino acid mutation on the p97 ATPase, promoting ATPase activity and cofactor dysregulation. The disease mechanism underlying p97 ATPase malfunction remains unclear. To understand how the mutation alters the ATPase reg-ulation, we assembled a full‐length p97R155H with its p47 cofactor and first visualized their structures using single‐particle cryo‐EM. More than one‐third of the population was the dodecameric form. Nucleotide presence dissociates the dodecamer into two hexamers for its highly elevated function. The N‐domains of the p97R155H mutant all show up configurations in ADP‐ or ATPγS‐bound states. Our functional and structural analyses showed that the p47 binding is likely to impact the p97R155H ATPase activities via changing the conformations of arginine fingers. These functional and structural analyses underline the ATPase dysregulation with the miscommunication between the functional modules of the p97R155H.
Original language | English (US) |
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Article number | 8079 |
Journal | International journal of molecular sciences |
Volume | 22 |
Issue number | 15 |
DOIs | |
State | Published - Aug 1 2021 |
Keywords
- Arginine finger
- IBMPFD
- P47 cofactor
- P97 ATPase
- P97 mutation
- Single‐particle cryo‐EM
ASJC Scopus subject areas
- Catalysis
- Molecular Biology
- Spectroscopy
- Computer Science Applications
- Physical and Theoretical Chemistry
- Organic Chemistry
- Inorganic Chemistry
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Dive into the research topics of 'Structural and functional analysis of disease‐linked p97 atpase mutant complexes'. Together they form a unique fingerprint.Datasets
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p97-R155H mutant dodecamer I
Nandi, P. (Contributor), Poh, Y. (Contributor), Li, S. (Contributor), Columbres, R. C. A. (Contributor), Wang, F. (Contributor), Williams, D. R. (Contributor), Chiu, P. (Contributor) & Chou, T. (Contributor), Protein Data Bank (PDB), Aug 4 2021
DOI: 10.2210/pdb7L5W, https://www.wwpdb.org/pdb?id=pdb_00007l5w
Dataset
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p47-bound p97-R155H mutant with ADP
Nandi, P. (Contributor), Poh, Y. (Contributor), Li, S. (Contributor), Columbres, R. C. A. (Contributor), Wang, F. (Contributor), Williams, D. R. (Contributor), Chiu, P. (Contributor) & Chou, T. (Contributor), Protein Data Bank (PDB), Aug 4 2021
DOI: 10.2210/pdb7R7T, https://www.wwpdb.org/pdb?id=pdb_00007r7t
Dataset
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D1 and D2 domain structure of the p97(R155H)-p47 complex
Nandi, P. (Contributor), Poh, Y. (Contributor), Li, S. (Contributor), Columbres, R. C. A. (Contributor), Wang, F. (Contributor), Williams, D. R. (Contributor), Chiu, P. (Contributor) & Chou, T. (Contributor), Protein Data Bank (PDB), Aug 4 2021
DOI: 10.2210/pdb7R7U, https://www.wwpdb.org/pdb?id=pdb_00007r7u
Dataset