ArticleProceedings of the National Academy of Sciences of the United States of America2015
L596-W733 bond between the start of the S4-S5 linker and the TRP box stabilizes the closed state of TRPV4 channel.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 53 citations in OpenAlex.
- Structural diversity of heat-sensing channel TRPV3 with Olmsted syndrome mutations.Nature communications · 2026Article
- Actually, what is a gain-of-function mutation?Genetics · 2026Article
- Recent advances on the structure and the function relationships of the TRPV4 ion channel.Channels (Austin, Tex.) · 2024Review
- PIPNature communications · 2024Article
- Relation between flexibility and intrinsically disorder regions in thermosensitive TRP channels reveal allosteric effects.European biophysics journal : EBJ · 2024Article
- Article
- Structures of the TRPM5 channel elucidate mechanisms of activation and inhibition.Nature structural & molecular biology · 2021Article
- TRPing to the Point of Clarity: Understanding the Function of the Complex TRPV4 Ion Channel.Cells · 2021Review
- Membrane cholesterol regulates TRPV4 function, cytoskeletal expression, and the cellular response to tension.Journal of lipid research · 2021Article
- Lipid Interactions of a Ciliary Membrane TRP Channel: Simulation and Structural Studies of Polycystin-2.Structure (London, England : 1993) · 2020Article
- Review
- Structural biology of thermoTRPV channels.Cell calcium · 2019Review
- Interaction of the Mechanosensitive Channel, MscS, with the Membrane Bilayer through Lipid Intercalation into Grooves and Pockets.Journal of molecular biology · 2019Article
- Human mutations highlight an intersubunit cation-π bond that stabilizes the closed but not open or inactivated states of TRPV channels.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Novel compounds that specifically bind and modulate MscL: insights into channel gating mechanisms.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2019Article
- Magnetic Entropy as a Proposed Gating Mechanism for Magnetogenetic Ion Channels.Biophysical journal · 2019Article
- Transient receptor potential vanilloid 4 (TRPV4) activation by arachidonic acid requires protein kinase A-mediated phosphorylation.The Journal of biological chemistry · 2018Article
- Article
- When size matters: transient receptor potential vanilloid 4 channel as a volume-sensor rather than an osmo-sensor.The Journal of physiology · 2017Article
- A competing hydrophobic tug on L596 to the membrane core unlatches S4-S5 linker elbow from TRP helix and allows TRPV4 channel to open.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
Abstract
Unlike other cation channels, each subunit of most transient receptor potential (TRP) channels has an additional TRP-domain helix with an invariant tryptophan immediately trailing the gate-bearing S6. Recent cryo-electron microscopy of TRP vanilloid subfamily, member 1 structures revealed that this domain is a five-turn amphipathic helix, and the invariant tryptophan forms a bond with the beginning of the four-turn S4-S5 linker helix. By homology modeling, we identified the corresponding L596-W733 bond in TRP vanilloid subfamily, member 4 (TRPV4). The L596P mutation blocks bone development in Kozlowski-type spondylometaphyseal dysplasia in human. Our previous screen also isolated W733R as a strong gain-of-function (GOF) mutation that suppresses growth when the W733R channel is expressed in yeast. We show that, when expressed in Xenopus oocytes, TRPV4 with the L596P or W733R mutation displays normal depolarization-induced activation and outward rectification. However, these mutant channels have higher basal open probabilities and limited responses to the agonist GSK1016790A, explaining their biological GOF phenotypes. In addition, W733R current fails to inactivate during depolarization. Systematic replacement of W733 with amino acids of different properties produced similar electrophysiological and yeast phenotypes. The results can be interpreted consistently in the context of the homology model of TRPV4 molecule we have developed and refined using simulations in explicit medium. We propose that this bond maintains the orientation of the S4-S5 linker to keep the S6 gate closed. Further, the two partner helices, both amphipathic and located at the polar-nonpolar interface of the inner lipid monolayer, may receive and integrate various physiological stimuli.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.