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Structure paper

TitleStructural basis of the activation of TRPV5 channels by long-chain acyl-Coenzyme-A.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 5883, Year 2023
Publish dateSep 21, 2023
AuthorsBo-Hyun Lee / José J De Jesús Pérez / Vera Moiseenkova-Bell / Tibor Rohacs /
PubMed AbstractLong-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 ...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)P) 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 in previous studies. This is consistent with our finding that PI(4,5)P 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.
External linksNat Commun / PubMed:37735536 / PubMed Central
MethodsEM (single particle)
Resolution3.09 - 3.5 Å
Structure data

29049

8ffo

EMDB-29049, PDB-8ffo:
Cryo-EM structure of wildtype rabbit TRPV5 with PI(4,5)P2 in nanodiscs
Method: EM (single particle) / Resolution: 3.5 Å

29085

8fhh

EMDB-29085, PDB-8fhh:
Wildtype rabbit TRPV5 in nanodiscs in the presence of oleoyl coenzyme A, Closed stated
Method: EM (single particle) / Resolution: 3.09 Å

29086

8fhi

EMDB-29086, PDB-8fhi:
Wildtype rabbit TRPV5 in nanodiscs in complex with oleoyl coenzyme A, Open stated
Method: EM (single particle) / Resolution: 3.25 Å

Chemicals

ChemComp-ERG:
ERGOSTEROL / Ergosterol

ChemComp-CPL:
1-PALMITOYL-2-LINOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / phospholipid*YM / Phosphatidylcholine

ChemComp-PIO:
[(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM / POPC

ChemComp-3VV:
S-{(3R,5R,9R)-1-[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-hydroxy-3-(phosphonooxy)tetrahydrofuran-2-yl]-3,5,9-trihydroxy-8,8-dimethyl-3,5-dioxido-10,14-dioxo-2,4,6-trioxa-11,15-diaza-3lambda~5~,5lambda~5~-diphosphaheptadecan-17-yl} (9Z)-octadec-9-enethioate (non-preferred name)

Source
  • oryctolagus cuniculus (rabbit)
KeywordsMEMBRANE PROTEIN / TRPV5 / TRP Channel / PI(4 / 5)P2 / oleoyl coenzyme A / Closed state / Open state

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