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

Sonya M. Hanson | Zendy; Mark S.P. Sansom | Zendy; Esther B. E. Becker | Zendy

Open Access

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

Author(s) -

Sonya M. Hanson,

Mark S.P. Sansom,

Esther B. E. Becker

Publication year - 2015

Publication title -

biochemistry

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 1.43

H-Index - 253

eISSN - 1520-4995

pISSN - 0006-2960

DOI - 10.1021/acs.biochem.5b00235

Subject(s) - trpc3 , mutant , phenotype , gating , ataxia , mutation , phosphorylation , microbiology and biotechnology , transient receptor potential channel , chemistry , biophysics , biology , neuroscience , biochemistry , receptor , gene , trpc

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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