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TitleStructural and Functional Analysis of Disease-Linked p97 ATPase Mutant Complexes.
Journal, issue, pagesInt J Mol Sci, Vol. 22, Issue 15, Year 2021
Publish dateJul 28, 2021
AuthorsPurbasha Nandi / Shan Li / Rod Carlo A Columbres / Feng Wang / Dewight R Williams / Yu-Ping Poh / Tsui-Fen Chou / Po-Lin Chiu /
PubMed AbstractIBMPFD/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 ...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 regulation, we assembled a full-length p97 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 p97 mutant all show up configurations in ADP- or ATPS-bound states. Our functional and structural analyses showed that the p47 binding is likely to impact the p97 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 p97.
External linksInt J Mol Sci / PubMed:34360842 / PubMed Central
MethodsEM (single particle)
Resolution3.34 - 6.1 Å
Structure data

EMDB-23191, PDB-7l5w:
p97-R155H mutant dodecamer I
Method: EM (single particle) / Resolution: 3.34 Å

EMDB-23192, PDB-7l5x:
p97-R155H mutant dodecamer II
Method: EM (single particle) / Resolution: 6.1 Å

EMDB-24302, PDB-7r7s:
p47-bound p97-R155H mutant with ATPgammaS
Method: EM (single particle) / Resolution: 4.23 Å

EMDB-24304, PDB-7r7t:
p47-bound p97-R155H mutant with ADP
Method: EM (single particle) / Resolution: 4.5 Å

EMDB-24305, PDB-7r7u:
D1 and D2 domain structure of the p97(R155H)-p47 complex
Method: EM (single particle) / Resolution: 4.3 Å

EMDB-24306:
Structure of the p97(R155H) dodecamer II
Method: EM (single particle) / Resolution: 6.1 Å

Chemicals

ChemComp-AGS:
PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-gamma-S, energy-carrying molecule analogue*YM

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM / Adenosine diphosphate

Source
  • homo sapiens (human)
  • rattus norvegicus (Norway rat)
KeywordsHYDROLASE / AAA+ ATPase / MOTOR PROTEIN / HYDROLASE/Lipid Binding Protein / HYDROLASE-Lipid Binding Protein complex

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