title: Modeling Suggests TRPC3 Hydrogen Bonding and Not Phosphorylation Contributes to the Ataxia Phenotype of the Moonwalker Mouse.
abstract: 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.
authors.affiliation: †Molecular Physiology and Biophysics Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, United States.|‡Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom.
authors.forename: Sonya M
authors.initials: SM
authors.lastname: Hanson
authors.affiliation: ‡Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom.
authors.forename: Mark S P
authors.initials: MS
authors.lastname: Sansom
authors.affiliation: §MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3PT, United Kingdom.
authors.forename: Esther B E
authors.initials: EB
authors.lastname: Becker
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006860:Hydrogen Bonding; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D010766:Phosphorylation; D017354:Point Mutation; D016415:Sequence Alignment; D050052:TRPC Cation Channels / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*
chemical_list: D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D002118:Calcium