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p97 Disease Mutations Modulate Nucleotide-Induced Conformation to Alter Protein–Protein Interactions

[Image: see text] The AAA+ ATPase p97/VCP adopts at least three conformations that depend on the binding of ADP and ATP and alter the orientation of the N-terminal protein–protein interaction (PPI) domain into “up” and “down” conformations. Point mutations that cause multisystem proteinopathy 1 (MSP...

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Autores principales: Bulfer, Stacie L., Chou, Tsui-Fen, Arkin, Michelle R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2016
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224236/
https://www.ncbi.nlm.nih.gov/pubmed/27267671
http://dx.doi.org/10.1021/acschembio.6b00350
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author Bulfer, Stacie L.
Chou, Tsui-Fen
Arkin, Michelle R.
author_facet Bulfer, Stacie L.
Chou, Tsui-Fen
Arkin, Michelle R.
author_sort Bulfer, Stacie L.
collection PubMed
description [Image: see text] The AAA+ ATPase p97/VCP adopts at least three conformations that depend on the binding of ADP and ATP and alter the orientation of the N-terminal protein–protein interaction (PPI) domain into “up” and “down” conformations. Point mutations that cause multisystem proteinopathy 1 (MSP1) are found at the interface of the N domain and D1-ATPase domain and potentially alter the conformational preferences of p97. Additionally, binding of “adaptor” proteins to the N-domain regulates p97’s catalytic activity. We propose that p97/adaptor PPIs are coupled to p97 conformational states. We evaluated the binding of nucleotides and the adaptor proteins p37 and p47 to wild-type p97 and MSP1 mutants. Notably, p47 and p37 bind 8-fold more weakly to the ADP-bound conformation of wild-type p97 compared to the ATP-bound conformation. However, MSP1 mutants lose this nucleotide-induced conformational coupling because they destabilize the ADP-bound, “down” conformation of the N-domain. Loss in conformation coupling to PPIs could contribute to the mechanism of MSP1.
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spelling pubmed-52242362017-06-07 p97 Disease Mutations Modulate Nucleotide-Induced Conformation to Alter Protein–Protein Interactions Bulfer, Stacie L. Chou, Tsui-Fen Arkin, Michelle R. ACS Chem Biol [Image: see text] The AAA+ ATPase p97/VCP adopts at least three conformations that depend on the binding of ADP and ATP and alter the orientation of the N-terminal protein–protein interaction (PPI) domain into “up” and “down” conformations. Point mutations that cause multisystem proteinopathy 1 (MSP1) are found at the interface of the N domain and D1-ATPase domain and potentially alter the conformational preferences of p97. Additionally, binding of “adaptor” proteins to the N-domain regulates p97’s catalytic activity. We propose that p97/adaptor PPIs are coupled to p97 conformational states. We evaluated the binding of nucleotides and the adaptor proteins p37 and p47 to wild-type p97 and MSP1 mutants. Notably, p47 and p37 bind 8-fold more weakly to the ADP-bound conformation of wild-type p97 compared to the ATP-bound conformation. However, MSP1 mutants lose this nucleotide-induced conformational coupling because they destabilize the ADP-bound, “down” conformation of the N-domain. Loss in conformation coupling to PPIs could contribute to the mechanism of MSP1. American Chemical Society 2016-06-07 2016-08-19 /pmc/articles/PMC5224236/ /pubmed/27267671 http://dx.doi.org/10.1021/acschembio.6b00350 Text en Copyright © 2016 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle Bulfer, Stacie L.
Chou, Tsui-Fen
Arkin, Michelle R.
p97 Disease Mutations Modulate Nucleotide-Induced Conformation to Alter Protein–Protein Interactions
title p97 Disease Mutations Modulate Nucleotide-Induced Conformation to Alter Protein–Protein Interactions
title_full p97 Disease Mutations Modulate Nucleotide-Induced Conformation to Alter Protein–Protein Interactions
title_fullStr p97 Disease Mutations Modulate Nucleotide-Induced Conformation to Alter Protein–Protein Interactions
title_full_unstemmed p97 Disease Mutations Modulate Nucleotide-Induced Conformation to Alter Protein–Protein Interactions
title_short p97 Disease Mutations Modulate Nucleotide-Induced Conformation to Alter Protein–Protein Interactions
title_sort p97 disease mutations modulate nucleotide-induced conformation to alter protein–protein interactions
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224236/
https://www.ncbi.nlm.nih.gov/pubmed/27267671
http://dx.doi.org/10.1021/acschembio.6b00350
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