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Structural insights on TRPV5 gating by endogenous modulators.

  • Author(s): Hughes, Taylor ET
  • Pumroy, Ruth A
  • Yazici, Aysenur Torun
  • Kasimova, Marina A
  • Fluck, Edwin C
  • Huynh, Kevin W
  • Samanta, Amrita
  • Molugu, Sudheer K
  • Zhou, Z Hong
  • Carnevale, Vincenzo
  • Rohacs, Tibor
  • Moiseenkova-Bell, Vera Y
  • et al.
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.

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