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TitleTransport mechanism of presynaptic high-affinity choline uptake by CHT1.
Journal, issue, pagesNat Struct Mol Biol, Vol. 31, Issue 4, Page 701-709, Year 2024
Publish dateApr 8, 2024
AuthorsYunlong Qiu / Yiwei Gao / Bo Huang / Qinru Bai / Yan Zhao /
PubMed AbstractCholine is a vital nutrient and a precursor for the biosynthesis of essential metabolites, including acetylcholine (ACh), that play a central role in fetal development, especially in the brain. In ...Choline is a vital nutrient and a precursor for the biosynthesis of essential metabolites, including acetylcholine (ACh), that play a central role in fetal development, especially in the brain. In cholinergic neurons, the high-affinity choline transporter (CHT1) provides an extraordinarily efficient reuptake mechanism to reutilize choline derived from intrasynaptical ACh hydrolysis and maintain ACh synthesis in the presynapse. Here, we determined structures of human CHT1 in three discrete states: the outward-facing state bound with the competitive inhibitor hemicholinium-3 (HC-3); the inward-facing occluded state bound with the substrate choline; and the inward-facing apo open state. Our structures and functional characterizations elucidate how the inhibitor and substrate are recognized. Moreover, our findings shed light on conformational changes when transitioning from an outward-facing to an inward-facing state and establish a framework for understanding the transport cycle, which relies on the stabilization of the outward-facing state by a short intracellular helix, IH1.
External linksNat Struct Mol Biol / PubMed:38589607
MethodsEM (single particle)
Resolution3.6 - 3.7 Å
Structure data

EMDB-36025, PDB-8j74:
Human high-affinity choline transporter CHT1 in the HC-3-bound outward-facing open conformation, dimeric state
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-36027, PDB-8j75:
Human high-affinity choline transporter CHT1 in the HC-3-bound outward-facing open conformation, monomeric state
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-36029, PDB-8j76:
Human high-affinity choline transporter CHT1 in the inward-facing apo-open conformation
Method: EM (single particle) / Resolution: 3.7 Å

EMDB-36030, PDB-8j77:
Human high-affinity choline transporter CHT1 in the choline-bound inward-facing occluded conformation
Method: EM (single particle) / Resolution: 3.7 Å

Chemicals

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-AV0:
Lauryl Maltose Neopentyl Glycol

ChemComp-R16:
HEXADECANE / Hexadecane

ChemComp-HC6:
(2S,2'S)-2,2'-biphenyl-4,4'-diylbis(2-hydroxy-4,4-dimethylmorpholin-4-ium)

ChemComp-CHT:
CHOLINE ION / Choline

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / CHT1 / SLC5A7 / high affinity choline transporter / choline transporter

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