8hik

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The TPP-bound BRIL-SLC19A1/Fab/Nb ternary complexThe TPP-bound BRIL-SLC19A1/Fab/Nb ternary complex

Structural highlights

8hik is a 4 chain structure with sequence from Escherichia coli, Homo sapiens and Lama glama. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 3.72Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

C562_ECOLX Electron-transport protein of unknown 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

Folate (vitamin B(9)) is the coenzyme involved in one-carbon transfer biochemical reactions essential for cell survival and proliferation, with its inadequacy causing developmental defects or severe diseases. Notably, mammalian cells lack the ability to de novo synthesize folate but instead rely on its intake from extracellular sources via specific transporters or receptors, among which SLC19A1 is the ubiquitously expressed one in tissues. However, the mechanism of substrate recognition by SLC19A1 remains unclear. Here we report the cryo-EM structures of human SLC19A1 and its complex with 5-methyltetrahydrofolate at 3.5-3.6 A resolution and elucidate the critical residues for substrate recognition. In particular, we reveal that two variant residues among SLC19 subfamily members designate the specificity for folate. Moreover, we identify intracellular thiamine pyrophosphate as the favorite coupled substrate for folate transport by SLC19A1. Together, this work establishes the molecular basis of substrate recognition by this central folate transporter.

Molecular mechanism of substrate recognition by folate transporter SLC19A1.,Dang Y, Zhou D, Du X, Zhao H, Lee CH, Yang J, Wang Y, Qin C, Guo Z, Zhang Z Cell Discov. 2022 Dec 28;8(1):141. doi: 10.1038/s41421-022-00508-w. PMID:36575193[15]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ 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:http://dx.doi.org/10.1074/jbc.M002328200
  2. ↑ 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:http://dx.doi.org/10.1016/j.exer.2003.08.013
  3. ↑ 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:http://dx.doi.org/10.1074/jbc.M408696200
  4. ↑ 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:http://dx.doi.org/10.1074/jbc.M507295200
  5. ↑ 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:http://dx.doi.org/10.1124/mol.112.078642
  6. ↑ 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:http://dx.doi.org/10.1016/j.molcel.2019.05.006
  7. ↑ 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:http://dx.doi.org/10.1038/s41586-019-1553-0
  8. ↑ 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:http://dx.doi.org/10.1182/blood.2019003178
  9. ↑ 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
  10. ↑ 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:http://dx.doi.org/10.1074/jbc.270.29.17468
  11. ↑ 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
  12. ↑ 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:http://dx.doi.org/10.1006/bbrc.1995.1096
  13. ↑ 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:http://dx.doi.org/10.1053/gast.1997.v112.pm9041240
  14. ↑ 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:http://dx.doi.org/10.1016/s0005-2736(98)00118-7
  15. ↑ Dang Y, Zhou D, Du X, Zhao H, Lee CH, Yang J, Wang Y, Qin C, Guo Z, Zhang Z. Molecular mechanism of substrate recognition by folate transporter SLC19A1. Cell Discov. 2022 Dec 28;8(1):141. PMID:36575193 doi:10.1038/s41421-022-00508-w

8hik, resolution 3.72Å

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