Modeling Suggests TRPC3 Hydrogen Bonding and Not Phosphorylation Contributes to the Ataxia Phenotype of the Moonwalker Mouse

[Image: see text] A gain-of-function mutation (T635A) in the transient receptor potential (TRP) channel TRPC3 results in abnormal channel gating and causes cerebellar ataxia in the dominant Moonwalker (Mwk) mouse mutant. However, the underlying molecular and structural mechanisms are unclear. Here,...

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Autores principales: Hanson, Sonya M., Sansom, Mark S. P., Becker, Esther B. E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2015
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530436/
https://www.ncbi.nlm.nih.gov/pubmed/26112884
http://dx.doi.org/10.1021/acs.biochem.5b00235
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author Hanson, Sonya M.
Sansom, Mark S. P.
Becker, Esther B. E.
author_facet Hanson, Sonya M.
Sansom, Mark S. P.
Becker, Esther B. E.
author_sort Hanson, Sonya M.
collection PubMed
description [Image: see text] A gain-of-function mutation (T635A) in the transient receptor potential (TRP) channel TRPC3 results in abnormal channel gating and causes cerebellar ataxia in the dominant Moonwalker (Mwk) mouse mutant. However, the underlying molecular and structural mechanisms are unclear. Here, we used a combined approach of computational modeling and functional characterization of proposed TRPC3 mutants. Our findings support a mechanism by which the hydrogen bonding capability of threonine 635 plays a significant role in maintaining a stable, closed state channel. This capability is lost in the Mwk mutant, suggesting a structural basis for the disease-causing phenotype in the Mwk mouse.
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spelling pubmed-45304362015-08-11 Modeling Suggests TRPC3 Hydrogen Bonding and Not Phosphorylation Contributes to the Ataxia Phenotype of the Moonwalker Mouse Hanson, Sonya M. Sansom, Mark S. P. Becker, Esther B. E. Biochemistry [Image: see text] A gain-of-function mutation (T635A) in the transient receptor potential (TRP) channel TRPC3 results in abnormal channel gating and causes cerebellar ataxia in the dominant Moonwalker (Mwk) mouse mutant. However, the underlying molecular and structural mechanisms are unclear. Here, we used a combined approach of computational modeling and functional characterization of proposed TRPC3 mutants. Our findings support a mechanism by which the hydrogen bonding capability of threonine 635 plays a significant role in maintaining a stable, closed state channel. This capability is lost in the Mwk mutant, suggesting a structural basis for the disease-causing phenotype in the Mwk mouse. American Chemical Society 2015-06-26 2015-07-07 /pmc/articles/PMC4530436/ /pubmed/26112884 http://dx.doi.org/10.1021/acs.biochem.5b00235 Text en Copyright © 2015 American Chemical Society This is an open access article published under a Creative Commons Non-Commercial No Derivative Works (CC-BY-NC-ND) Attribution License (http://pubs.acs.org/page/policy/authorchoice_ccbyncnd_termsofuse.html) , which permits copying and redistribution of the article, and creation of adaptations, all for non-commercial purposes.
spellingShingle Hanson, Sonya M.
Sansom, Mark S. P.
Becker, Esther B. E.
Modeling Suggests TRPC3 Hydrogen Bonding and Not Phosphorylation Contributes to the Ataxia Phenotype of the Moonwalker Mouse
title Modeling Suggests TRPC3 Hydrogen Bonding and Not Phosphorylation Contributes to the Ataxia Phenotype of the Moonwalker Mouse
title_full Modeling Suggests TRPC3 Hydrogen Bonding and Not Phosphorylation Contributes to the Ataxia Phenotype of the Moonwalker Mouse
title_fullStr Modeling Suggests TRPC3 Hydrogen Bonding and Not Phosphorylation Contributes to the Ataxia Phenotype of the Moonwalker Mouse
title_full_unstemmed Modeling Suggests TRPC3 Hydrogen Bonding and Not Phosphorylation Contributes to the Ataxia Phenotype of the Moonwalker Mouse
title_short Modeling Suggests TRPC3 Hydrogen Bonding and Not Phosphorylation Contributes to the Ataxia Phenotype of the Moonwalker Mouse
title_sort modeling suggests trpc3 hydrogen bonding and not phosphorylation contributes to the ataxia phenotype of the moonwalker mouse
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530436/
https://www.ncbi.nlm.nih.gov/pubmed/26112884
http://dx.doi.org/10.1021/acs.biochem.5b00235
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AT beckerestherbe modelingsuggeststrpc3hydrogenbondingandnotphosphorylationcontributestotheataxiaphenotypeofthemoonwalkermouse

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