Structural insights on TRPV5 gating by endogenous modulators

Taylor E. T. Hughes, Ruth A. Pumroy, Aysenur Torun Yazici, Marina A. Kasimova, Edwin C. Fluck, Kevin W. Huynh, Amrita Samanta, Sudheer K. Molugu, Z. Hong Zhou, Vincenzo Carnevale, Tibor Rohacs and Vera Y. Moiseenkova-Bell ()
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Taylor E. T. Hughes: University of Pennsylvania
Ruth A. Pumroy: University of Pennsylvania
Aysenur Torun Yazici: Rutgers University
Marina A. Kasimova: Temple University
Edwin C. Fluck: University of Pennsylvania
Kevin W. Huynh: University of California
Amrita Samanta: University of Pennsylvania
Sudheer K. Molugu: University of Pennsylvania
Z. Hong Zhou: University of California
Vincenzo Carnevale: Temple University
Tibor Rohacs: Rutgers University
Vera Y. Moiseenkova-Bell: University of Pennsylvania

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06753-6

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