Structural basis of the activation of TRPV5 channels by long-chain acyl-Coenzyme-A

Long-chain acyl-coenzyme A (LC-CoA) is a crucial metabolic intermediate that plays important cellular regulatory roles, including activation and inhibition of ion channels. The structural basis of ion channel regulation by LC-CoA is not known. Transient receptor potential vanilloid 5 and 6 (TRPV5 and TRPV6) are epithelial calcium-selective ion channels. Here, we demonstrate that LC-CoA activates TRPV5 and TRPV6 in inside-out patches, and both exogenously supplied and endogenously produced LC-CoA can substitute for the natural ligand phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) in maintaining channel activity in intact cells. Utilizing cryo-electron microscopy, we determined the structure of LC-CoA-bound TRPV5, revealing an open configuration with LC-CoA occupying the same binding site as PI(4,5)P2 in previous studies. This is consistent with our finding that PI(4,5)P2 could not further activate the channels in the presence of LC-CoA. Our data provide molecular insights into ion channel regulation by a metabolic signaling molecule. Long-chain acyl-Coenzyme-A is a metabolic intermediate with important signaling functions. Here the authors show that it activates the Ca2+ selective ion channels TRPV5 and TRPV6 and elucidate the structural basis of TRPV5 activation using CryoEM.

Automated summary

Long-chain acyl-Coenzyme A (LC-CoA) is an important signaling molecule that activates TRPV5 and TRPV6 ion channels. The researchers discovered that LC-CoA and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) have the same mechanism in maintaining channel activity. By utilizing cryo-electron microscopy, the authors determined the structure of LC-CoA-bound TRPV5, providing insights into the regulation of ion channels by metabolic signaling molecules.