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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.

Original publication

DOI

10.1021/acs.biochem.5b00235

Type

Journal article

Journal

Biochemistry

Publication Date

07/07/2015

Volume

54

Pages

4033 - 4041

Keywords

Amino Acid Sequence, Animals, Calcium, Cell Line, Cerebellar Ataxia, Hydrogen Bonding, Mice, Models, Molecular, Molecular Sequence Data, Neurons, Phenotype, Phosphorylation, Point Mutation, Sequence Alignment, TRPC Cation Channels