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Structural insights on TRPV5 gating by endogenous modulators.

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Hughes TET, Pumroy RA, Yazici AT, Kasimova MA, Fluck EC, Huynh KW, Samanta A, Molugu SK, Zhou ZH, Carnevale V, Rohacs T, Moiseenkova-Bell VY
OpenAccess logo Nat Commun 9 4198 (2018)
Related entries: 6dmu, 6dmw

Cited: 83 times
EuropePMC logo PMID: 30305626

Abstract

TRPV5 is a transient receptor potential channel involved in calcium reabsorption. Here we investigate the interaction of two endogenous modulators with TRPV5. Both phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and calmodulin (CaM) have been shown to directly bind to TRPV5 and activate or inactivate the channel, respectively. Using cryo-electron microscopy (cryo-EM), we determined TRPV5 structures in the presence of dioctanoyl PI(4,5)P2 and CaM. The PI(4,5)P2 structure reveals a binding site between the N-linker, S4-S5 linker and S6 helix of TRPV5. These interactions with PI(4,5)P2 induce conformational rearrangements in the lower gate, opening the channel. The CaM structure reveals two TRPV5 C-terminal peptides anchoring a single CaM molecule and that calcium inhibition is mediated through a cation-π interaction between Lys116 on the C-lobe of calcium-activated CaM and Trp583 at the intracellular gate of TRPV5. Overall, this investigation provides insight into the endogenous modulation of TRPV5, which has the potential to guide drug discovery.

Reviews - 6dmr mentioned but not cited (1)

  1. Structural insights into the gating mechanisms of TRPV channels. Pumroy RA, Fluck EC, Ahmed T, Moiseenkova-Bell VY. Cell Calcium 87 102168 (2020)

Articles - 6dmr mentioned but not cited (5)



Reviews citing this publication (23)

  1. Novel roles of phosphoinositides in signaling, lipid transport, and disease. Hammond GRV, Burke JE. Curr Opin Cell Biol 63 57-67 (2020)
  2. Transient Receptor Potential Channels and Calcium Signaling. Vangeel L, Voets T. Cold Spring Harb Perspect Biol 11 a035048 (2019)
  3. Tools for Understanding Nanoscale Lipid Regulation of Ion Channels. Robinson CV, Rohacs T, Hansen SB. Trends Biochem Sci 44 795-806 (2019)
  4. Structural mechanisms of transient receptor potential ion channels. Cao E. J Gen Physiol 152 e201811998 (2020)
  5. The role of π-helices in TRP channel gating. Zubcevic L, Lee SY. Curr Opin Struct Biol 58 314-323 (2019)
  6. Direct Structural Insights into GABAA Receptor Pharmacology. Kim JJ, Hibbs RE. Trends Biochem Sci 46 502-517 (2021)
  7. Calcium selective channel TRPV6: Structure, function, and implications in health and disease. Khattar V, Wang L, Peng JB. Gene 817 146192 (2022)
  8. Sensory TRP Channels in Three Dimensions. Diver MM, Lin King JV, Julius D, Cheng Y. Annu Rev Biochem 91 629-649 (2022)
  9. Structure and function of the calcium-selective TRP channel TRPV6. Yelshanskaya MV, Nadezhdin KD, Kurnikova MG, Sobolevsky AI. J Physiol 599 2673-2697 (2021)
  10. Ligand-Binding Sites in Vanilloid-Subtype TRP Channels. Yelshanskaya MV, Sobolevsky AI. Front Pharmacol 13 900623 (2022)
  11. Current View of Ligand and Lipid Recognition by the Menthol Receptor TRPM8. Yin Y, Lee SY. Trends Biochem Sci 45 806-819 (2020)
  12. TRP ion channels: Proteins with conformational flexibility. López-Romero AE, Hernández-Araiza I, Torres-Quiroz F, Tovar-Y-Romo LB, Islas LD, Rosenbaum T. Channels (Austin) 13 207-226 (2019)
  13. High-resolution structures of transient receptor potential vanilloid channels: Unveiling a functionally diverse group of ion channels. van Goor MK, de Jager L, Cheng Y, van der Wijst J. Protein Sci 29 1569-1580 (2020)
  14. Druggable Lipid Binding Sites in Pentameric Ligand-Gated Ion Channels and Transient Receptor Potential Channels. Cheng WWL, Arcario MJ, Petroff JT. Front Physiol 12 798102 (2021)
  15. Structures and Dynamics of Native-State Transmembrane Protein Targets and Bound Lipids. Overduin M, Trieber C, Prosser RS, Picard LP, Sheff JG. Membranes (Basel) 11 451 (2021)
  16. Regulation of the cold-sensing TRPM8 channels by phosphoinositides and Gq-coupled receptors. Liu L, Rohacs T. Channels (Austin) 14 79-86 (2020)
  17. Atomistic Insights of Calmodulin Gating of Complete Ion Channels. Núñez E, Muguruza-Montero A, Villarroel A. Int J Mol Sci 21 E1285 (2020)
  18. Two Decades of Evolution of Our Understanding of the Transient Receptor Potential Melastatin 2 (TRPM2) Cation Channel. Szollosi A. Life (Basel) 11 397 (2021)
  19. The Role of Lipids in CRAC Channel Function. Maltan L, Andova AM, Derler I. Biomolecules 12 352 (2022)
  20. Alterations in the microenvironment and the effects produced of TRPV5 in osteoporosis. Luo ZH, Ma JX, Zhang W, Tian AX, Gong SW, Li Y, Lai YX, Ma XL. J Transl Med 21 327 (2023)
  21. Interaction of Calmodulin with TRPM: An Initiator of Channel Modulation. Vydra Bousova K, Zouharova M, Jiraskova K, Vetyskova V. Int J Mol Sci 24 15162 (2023)
  22. Molecular pharmacology of the onco-TRP channel TRPV6. Neuberger A, Sobolevsky AI. Channels (Austin) 17 2266669 (2023)
  23. Targeting ion channels with ultra-large library screening for hit discovery. Melancon K, Pliushcheuskaya P, Meiler J, Künze G. Front Mol Neurosci 16 1336004 (2023)

Articles citing this publication (54)



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