Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-06753-6
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Funding
- National Institutes of Health Core Grant [P30EY11373]
- NIH [1S10RR23057, 1S10OD018111]
- NSF [DBI-1338135, DMR-1548924]
- CNSI at UCLA
- National Cancer Institute's National Cryo-EM Facility at the Frederick National Laboratory for Cancer Research
- National Institute of Health [R01GM103899, R01GM093290, U24 GM116792]
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TRPV5 is a transient receptor potential channel involved in calcium reabsorption. Here we investigate the interaction of two endogenous modulators with TRPV5. Both phosphatidyli-nositol 4,5-bisphosphate (PI(4,5)P-2) 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 P1(4,5)P-2 and CaM. The P1(4,5)P-2 structure reveals a binding site between the N-linker, S4-S5 linker and S6 helix of TRPV5. These interactions with P1(4,5)P-2 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-pi 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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