| Structural highlights
Disease
S19A1_HUMAN 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
S19A1_HUMAN Antiporter that mediates the import of reduced folates or a subset of cyclic dinucleotides, driven by the export of organic anions (PubMed:10787414, PubMed:15337749, PubMed:16115875, PubMed:22554803, PubMed:31126740, PubMed:31511694, PubMed:32276275, PubMed:7826387, PubMed:9041240). Mechanistically, acts as a secondary active transporter, which exports intracellular organic anions down their concentration gradients to facilitate the uptake of its substrates (PubMed:22554803, PubMed:31126740, PubMed:31511694). Has high affinity for N5-methyltetrahydrofolate, the predominant circulating form of folate (PubMed:10787414, PubMed:14609557, PubMed:22554803). Also able to mediate the import of antifolate drug methotrexate (PubMed:22554803, PubMed:7615551, PubMed:7641195, PubMed:9767079). Also acts as an importer of immunoreactive cyclic dinucleotides, such as cyclic GMP-AMP (2'-3'-cGAMP), an immune messenger produced in response to DNA virus in the cytosol, and its linkage isomer 3'-3'-cGAMP, thus playing a role in triggering larger immune responses (PubMed:31126740, PubMed:31511694, PubMed:36745868). 5-amino-4-imidazolecarboxamide riboside (AICAR), when phosphorylated to AICAR monophosphate, can serve as an organic anion for antiporter activity (PubMed:22554803).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]
Publication Abstract from PubMed
Cyclic dinucleotides (CDNs) are ubiquitous signalling molecules in all domains of life(1,2). Mammalian cells produce one CDN, 2'3'-cGAMP, through cyclic GMP-AMP synthase after detecting cytosolic DNA signals(3-7). 2'3'-cGAMP, as well as bacterial and synthetic CDN analogues, can act as second messengers to activate stimulator of interferon genes (STING) and elicit broad downstream responses(8-21). Extracellular CDNs must traverse the cell membrane to activate STING, a process that is dependent on the solute carrier SLC19A1(22,23). Moreover, SLC19A1 represents the major transporter for folate nutrients and antifolate therapeutics(24,25), thereby placing SLC19A1 as a key factor in multiple physiological and pathological processes. How SLC19A1 recognizes and transports CDNs, folate and antifolate is unclear. Here we report cryo-electron microscopy structures of human SLC19A1 (hSLC19A1) in a substrate-free state and in complexes with multiple CDNs from different sources, a predominant natural folate and a new-generation antifolate drug. The structural and mutagenesis results demonstrate that hSLC19A1 uses unique yet divergent mechanisms to recognize CDN- and folate-type substrates. Two CDN molecules bind within the hSLC19A1 cavity as a compact dual-molecule unit, whereas folate and antifolate bind as a monomer and occupy a distinct pocket of the cavity. Moreover, the structures enable accurate mapping and potential mechanistic interpretation of hSLC19A1 with loss-of-activity and disease-related mutations. Our research provides a framework for understanding the mechanism of SLC19-family transporters and is a foundation for the development of potential therapeutics.
Recognition of cyclic dinucleotides and folates by human SLC19A1.,Zhang Q, Zhang X, Zhu Y, Sun P, Zhang L, Ma J, Zhang Y, Zeng L, Nie X, Gao Y, Li Z, Liu S, Lou J, Gao A, Zhang L, Gao P Nature. 2022 Dec;612(7938):170-176. doi: 10.1038/s41586-022-05452-z. Epub 2022 , Oct 20. PMID:36265513[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Chancy CD, Kekuda R, Huang W, Prasad PD, Kuhnel JM, Sirotnak FM, Roon P, Ganapathy V, Smith SB. Expression and differential polarization of the reduced-folate transporter-1 and the folate receptor alpha in mammalian retinal pigment epithelium. J Biol Chem. 2000 Jul 7;275(27):20676-84. doi: 10.1074/jbc.M002328200. PMID:10787414 doi:https://dx.doi.org/10.1074/jbc.M002328200
- ↑ Naggar H, Fei YJ, Ganapathy V, Smith SB. Regulation of reduced-folate transporter-1 (RFT-1) by homocysteine and identity of transport systems for homocysteine uptake in retinal pigment epithelial (RPE) cells. Exp Eye Res. 2003 Dec;77(6):687-97. doi: 10.1016/j.exer.2003.08.013. PMID:14609557 doi:https://dx.doi.org/10.1016/j.exer.2003.08.013
- ↑ Witt TL, Stapels SE, Matherly LH. Restoration of transport activity by co-expression of human reduced folate carrier half-molecules in transport-impaired K562 cells: localization of a substrate binding domain to transmembrane domains 7-12. J Biol Chem. 2004 Nov 5;279(45):46755-63. doi: 10.1074/jbc.M408696200. Epub 2004 , Aug 26. PMID:15337749 doi:https://dx.doi.org/10.1074/jbc.M408696200
- ↑ Hou Z, Stapels SE, Haska CL, Matherly LH. Localization of a substrate binding domain of the human reduced folate carrier to transmembrane domain 11 by radioaffinity labeling and cysteine-substituted accessibility methods. J Biol Chem. 2005 Oct 28;280(43):36206-13. doi: 10.1074/jbc.M507295200. Epub 2005, Aug 22. PMID:16115875 doi:https://dx.doi.org/10.1074/jbc.M507295200
- ↑ Visentin M, Zhao R, Goldman ID. Augmentation of reduced folate carrier-mediated folate/antifolate transport through an antiport mechanism with 5-aminoimidazole-4-carboxamide riboside monophosphate. Mol Pharmacol. 2012 Aug;82(2):209-16. doi: 10.1124/mol.112.078642. Epub 2012 May , 3. PMID:22554803 doi:https://dx.doi.org/10.1124/mol.112.078642
- ↑ Ritchie C, Cordova AF, Hess GT, Bassik MC, Li L. SLC19A1 Is an Importer of the Immunotransmitter cGAMP. Mol Cell. 2019 Jul 25;75(2):372-381.e5. doi: 10.1016/j.molcel.2019.05.006. Epub, 2019 May 21. PMID:31126740 doi:https://dx.doi.org/10.1016/j.molcel.2019.05.006
- ↑ Luteijn RD, Zaver SA, Gowen BG, Wyman SK, Garelis NE, Onia L, McWhirter SM, Katibah GE, Corn JE, Woodward JJ, Raulet DH. SLC19A1 transports immunoreactive cyclic dinucleotides. Nature. 2019 Sep;573(7774):434-438. doi: 10.1038/s41586-019-1553-0. Epub 2019 Sep, 11. PMID:31511694 doi:https://dx.doi.org/10.1038/s41586-019-1553-0
- ↑ Svaton M, Skvarova Kramarzova K, Kanderova V, Mancikova A, Smisek P, Jesina P, Krijt J, Stiburkova B, Dobrovolny R, Sokolova J, Bakardjieva-Mihaylova V, Vodickova E, Rackova M, Stuchly J, Kalina T, Stary J, Trka J, Fronkova E, Kozich V. A homozygous deletion in the SLC19A1 gene as a cause of folate-dependent recurrent megaloblastic anemia. Blood. 2020 Jun 25;135(26):2427-2431. doi: 10.1182/blood.2019003178. PMID:32276275 doi:https://dx.doi.org/10.1182/blood.2019003178
- ↑ Shiraishi A, Uygun V, Sharfe N, Beldar S, Sun MGF, Dadi H, Vong L, Maxson M, Karaca NE, Mevlitoğlu S, Grinstein S, Artan R, Merico D, Roifman CM. Novel immunodeficiency caused by homozygous mutation in solute carrier family 19 member 1, which encodes the reduced folate carrier. Blood. 2023 Jun 29;141(26):3226-3230. PMID:36745868 doi:10.1182/blood.2022017968
- ↑ Wong SC, Proefke SA, Bhushan A, Matherly LH. Isolation of human cDNAs that restore methotrexate sensitivity and reduced folate carrier activity in methotrexate transport-defective Chinese hamster ovary cells. J Biol Chem. 1995 Jul 21;270(29):17468-75. doi: 10.1074/jbc.270.29.17468. PMID:7615551 doi:https://dx.doi.org/10.1074/jbc.270.29.17468
- ↑ Moscow JA, Gong M, He R, Sgagias MK, Dixon KH, Anzick SL, Meltzer PS, Cowan KH. Isolation of a gene encoding a human reduced folate carrier (RFC1) and analysis of its expression in transport-deficient, methotrexate-resistant human breast cancer cells. Cancer Res. 1995 Sep 1;55(17):3790-4. PMID:7641195
- ↑ Prasad PD, Ramamoorthy S, Leibach FH, Ganapathy V. Molecular cloning of the human placental folate transporter. Biochem Biophys Res Commun. 1995 Jan 17;206(2):681-7. doi:, 10.1006/bbrc.1995.1096. PMID:7826387 doi:https://dx.doi.org/10.1006/bbrc.1995.1096
- ↑ Nguyen TT, Dyer DL, Dunning DD, Rubin SA, Grant KE, Said HM. Human intestinal folate transport: cloning, expression, and distribution of complementary RNA. Gastroenterology. 1997 Mar;112(3):783-91. doi: 10.1053/gast.1997.v112.pm9041240. PMID:9041240 doi:https://dx.doi.org/10.1053/gast.1997.v112.pm9041240
- ↑ Wong SC, Zhang L, Proefke SA, Matherly LH. Effects of the loss of capacity for N-glycosylation on the transport activity and cellular localization of the human reduced folate carrier. Biochim Biophys Acta. 1998 Oct 15;1375(1-2):6-12. doi:, 10.1016/s0005-2736(98)00118-7. PMID:9767079 doi:https://dx.doi.org/10.1016/s0005-2736(98)00118-7
- ↑ Zhang Q, Zhang X, Zhu Y, Sun P, Zhang L, Ma J, Zhang Y, Zeng L, Nie X, Gao Y, Li Z, Liu S, Lou J, Gao A, Zhang L, Gao P. Recognition of cyclic dinucleotides and folates by human SLC19A1. Nature. 2022 Dec;612(7938):170-176. PMID:36265513 doi:10.1038/s41586-022-05452-z
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