8ffo | pdb_00008ffo
Cryo-EM structure of wildtype rabbit TRPV5 with PI(4,5)P2 in nanodiscs
Structural highlights
FunctionTRPV5_RABIT Constitutively active calcium selective cation channel thought to be involved in Ca(2+) reabsorption in kidney and intestine (PubMed:12574114). Required for normal Ca(2+) reabsorption in the kidney distal convoluted tubules (By similarity). The channel is activated by low internal calcium level and the current exhibits an inward rectification (By similarity). A Ca(2+)-dependent feedback regulation includes fast channel inactivation and slow current decay (By similarity). Heteromeric assembly with TRPV6 seems to modify channel properties. TRPV5-TRPV6 heteromultimeric concatemers exhibit voltage-dependent gating (PubMed:12574114).[UniProtKB:P69744][UniProtKB:Q9NQA5][1] [2] [3] Publication Abstract from PubMedLong-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)P(2)) 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)P(2) in previous studies. This is consistent with our finding that PI(4,5)P(2) 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. Structural basis of the activation of TRPV5 channels by long-chain acyl-Coenzyme-A.,Lee BH, De Jesus Perez JJ, Moiseenkova-Bell V, Rohacs T Nat Commun. 2023 Sep 21;14(1):5883. doi: 10.1038/s41467-023-41577-z. PMID:37735536[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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