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Title | Structural insights on TRPV5 gating by endogenous modulators. |
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Journal, issue, pages | Nat Commun, Vol. 9, Issue 1, Page 4198, Year 2018 |
Publish date | Oct 10, 2018 |
Authors | 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 / Vera Y Moiseenkova-Bell / |
PubMed 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- ...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)P) 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)P and CaM. The PI(4,5)P structure reveals a binding site between the N-linker, S4-S5 linker and S6 helix of TRPV5. These interactions with PI(4,5)P 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. |
External links | Nat Commun / PubMed:30305626 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.9 - 4.4 Å |
Structure data | |
Chemicals | ChemComp-PIO: ChemComp-CA: |
Source |
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Keywords | TRANSPORT PROTEIN / TRPV5 / calcium channel / lipid-bound / full-length / PI(4 / 5)P2 / ion channel / calmodulin |