| Structural highlights
8j74 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | Electron Microscopy, Resolution 3.6Å |
| Ligands: | AV0, BMA, HC6, NAG, R16, Y01 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
SC5A7_HUMAN Distal hereditary motor neuropathy type 7;Presynaptic congenital myasthenic syndromes. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry.
Function
SC5A7_HUMAN High-affinity Na(+)-coupled choline transmembrane symporter (PubMed:11027560, PubMed:11068039, PubMed:12237312, PubMed:12969261, PubMed:17005849, PubMed:23132865, PubMed:23141292, PubMed:27569547). Functions as an electrogenic, voltage-dependent transporter with variable charge/choline stoichiometry (PubMed:17005849). Choline uptake and choline-induced current is also Cl(-)-dependent where Cl(-) is likely a regulatory ion rather than cotransported ion (PubMed:11068039, PubMed:12237312, PubMed:17005849). Plays a critical role in acetylcholine (ACh) synthesis by taking up the substrate choline from the synaptic cleft into the presynaptic nerve terminals after neurotransmitter release (PubMed:27569547). SLC5A7/CHT1-mediated choline high-affinity transport in cholinergic neurons is the rate-limiting step for production of ACh, thereby facilitating communication by subsequent action potentials (PubMed:11027560). Localized predominantly in presynaptic terminal intracellular organelles, and translocated to the plasma membrane in active form in response to neuronal activity (PubMed:12969261, PubMed:15953352).[1] [2] [3] [4] [5] [6] [7] [8] [9]
Publication Abstract from PubMed
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.
Transport mechanism of presynaptic high-affinity choline uptake by CHT1.,Qiu Y, Gao Y, Huang B, Bai Q, Zhao Y Nat Struct Mol Biol. 2024 Apr;31(4):701-709. doi: 10.1038/s41594-024-01259-w. , Epub 2024 Apr 8. PMID:38589607[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Apparsundaram S, Ferguson SM, George AL Jr, Blakely RD. Molecular cloning of a human, hemicholinium-3-sensitive choline transporter. Biochem Biophys Res Commun. 2000 Oct 5;276(3):862-7. PMID:11027560 doi:10.1006/bbrc.2000.3561
- ↑ Okuda T, Haga T. Functional characterization of the human high-affinity choline transporter. FEBS Lett. 2000 Nov 3;484(2):92-7. PMID:11068039 doi:10.1016/s0014-5793(00)02134-7
- ↑ Okuda T, Okamura M, Kaitsuka C, Haga T, Gurwitz D. Single nucleotide polymorphism of the human high affinity choline transporter alters transport rate. J Biol Chem. 2002 Nov 22;277(47):45315-22. PMID:12237312 doi:10.1074/jbc.M207742200
- ↑ Ribeiro FM, Alves-Silva J, Volknandt W, Martins-Silva C, Mahmud H, Wilhelm A, Gomez MV, Rylett RJ, Ferguson SS, Prado VF, Prado MA. The hemicholinium-3 sensitive high affinity choline transporter is internalized by clathrin-mediated endocytosis and is present in endosomes and synaptic vesicles. J Neurochem. 2003 Oct;87(1):136-46. PMID:12969261 doi:10.1046/j.1471-4159.2003.01974.x
- ↑ Ribeiro FM, Black SA, Cregan SP, Prado VF, Prado MA, Rylett RJ, Ferguson SS. Constitutive high-affinity choline transporter endocytosis is determined by a carboxyl-terminal tail dileucine motif. J Neurochem. 2005 Jul;94(1):86-96. PMID:15953352 doi:10.1111/j.1471-4159.2005.03171.x
- ↑ Iwamoto H, Blakely RD, De Felice LJ. Na+, Cl-, and pH dependence of the human choline transporter (hCHT) in Xenopus oocytes: the proton inactivation hypothesis of hCHT in synaptic vesicles. J Neurosci. 2006 Sep 27;26(39):9851-9. PMID:17005849 doi:10.1523/JNEUROSCI.1862-06.2006
- ↑ Okuda T, Osawa C, Yamada H, Hayashi K, Nishikawa S, Ushio T, Kubo Y, Satou M, Ogawa H, Haga T. Transmembrane topology and oligomeric structure of the high-affinity choline transporter. J Biol Chem. 2012 Dec 14;287(51):42826-34. PMID:23132865 doi:10.1074/jbc.M112.405027
- ↑ Barwick KE, Wright J, Al-Turki S, McEntagart MM, Nair A, Chioza B, Al-Memar A, Modarres H, Reilly MM, Dick KJ, Ruggiero AM, Blakely RD, Hurles ME, Crosby AH. Defective presynaptic choline transport underlies hereditary motor neuropathy. Am J Hum Genet. 2012 Dec 7;91(6):1103-7. PMID:23141292 doi:10.1016/j.ajhg.2012.09.019
- ↑ Bauché S, O'Regan S, Azuma Y, Laffargue F, McMacken G, Sternberg D, Brochier G, Buon C, Bouzidi N, Topf A, Lacène E, Remerand G, Beaufrere AM, Pebrel-Richard C, Thevenon J, El Chehadeh-Djebbar S, Faivre L, Duffourd Y, Ricci F, Mongini T, Fiorillo C, Astrea G, Burloiu CM, Butoianu N, Sandu C, Servais L, Bonne G, Nelson I, Desguerre I, Nougues MC, Bœuf B, Romero N, Laporte J, Boland A, Lechner D, Deleuze JF, Fontaine B, Strochlic L, Lochmuller H, Eymard B, Mayer M, Nicole S. Impaired Presynaptic High-Affinity Choline Transporter Causes a Congenital Myasthenic Syndrome with Episodic Apnea. Am J Hum Genet. 2016 Sep 1;99(3):753-761. PMID:27569547 doi:10.1016/j.ajhg.2016.06.033
- ↑ Qiu Y, Gao Y, Huang B, Bai Q, Zhao Y. Transport mechanism of presynaptic high-affinity choline uptake by CHT1. Nat Struct Mol Biol. 2024 Apr;31(4):701-709. PMID:38589607 doi:10.1038/s41594-024-01259-w
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