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- W2014736703 abstract "Unlike other cation channels, all TRP (Transient Receptor Potential) channel subunits have a TRP-domain helix immediately trailing S6 that bears the gate. The role(s) of TRP-domain helix is unclear. Recent cryo-EM TRPV1 structures revealed that this helix forms a bond with the beginning of the S4-S5 linker. By homology modeling, we identified the corresponding L596-W733 bond in TRPV4 (Vanilloid type 4). L596P, likely a gain-of-function (GOF) mutation, causes bone-developmental blockage of the spondylometaphyseal dysplasia Kozlowski type (SMDK) in human. Our previous screen also isolated W733R as a GOF that suppresses grows of yeast expressing TRPV4. Here we show, when expressed in Xenopus oocytes, TRPV4 with L596P or W733R mutation displays normal depolarization-induced activation and outward rectification. However, as expected from their biological GOF phenotypes, these mutant channels indeed have higher basal open probabilities and limited responses to the strong agonist GSK1016790A. In addition, W733R current also fails to inactivate after activation during depolarization. Systematic substitutions of W733 with amino acids of different properties produce similar electrophysiological defects. The results can be consistently interpreted in the context of the homology model of TRPV4 that we have developed. Our results indicate that the TRP domain stabilizes various functional conformations by bonding to other structures, especially to the S4-S5 linker." @default.
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- W2014736703 date "2015-01-01" @default.
- W2014736703 modified "2023-09-28" @default.
- W2014736703 title "The L596-W733 Bond between S4-S5 Linker and TRP Domain Maintains Basal Activity and Enables Inactivation of TRPV4" @default.
- W2014736703 doi "https://doi.org/10.1016/j.bpj.2014.11.230" @default.
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