SLC6A20
| SLC6A20 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | SLC6A20, SIT1, XT3, Xtrp3, solute carrier family 6 member 20, IMINO | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 605616; MGI: 2143217; HomoloGene: 10625; GeneCards: SLC6A20; OMA:SLC6A20 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Solute carrier family 6, member 20 also known as SLC6A20 is a gene[5][6] that encodes for the Sodium/imino-acid transporter 1 (SIT1) protein, a plasma membrane proline and glycine transporter.[7]
Function
The Sodium/imino-acid transporter 1 (SIT1) protein is a member of the solute carrier superfamily of transport proteins. SIT1 is a Na+ and Cl− coupled symporter,[8] like other SLC6 amino acid and amine transporters, and a homolog of the Bacterial Leucine Transporter.[9]
Among the SLC6 transporters, only SIT1 and SLC6A7 (PROT) prefer secondary amino acids.[8] This selectivity arises due to the shape and highly conserved residues of the protein's binding site to exclude residues with extended site chains.[10]
Natively, SIT1 forms a complex with ACE2 or collectrin, which assists in trafficking the transporter to the plasma membrane.[11]
Clinical significance
Mutation in the SLC6A20 gene are associated with iminoglycinuria.[12][9]
One of a cluster of 6 genes (SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1) on chromosome 3 at location 3p21.31 associated with a genetic susceptibility to COVID-19 respiratory failure.[13][14][15] Of these, SIT1 expression can control ACE2 trafficking to the plasma membrane and thereby SLC6A20 gene variants are proposed to alter the availability of viral receptors on the cell surface.[16]
SIT1 is proposed to modulate the activity of glycine and NMDA receptors,[17] and variants in the SLC6A20 gene are associated with Hirschprung's disease.[18][19][20]
SIT1 is also the primary proline transporter in the retinal pigment epithelium[21] and supports the proline-dependent metabolism of these cells.[22] Consequently, SLC6A20 gene variants are associated with retinal thickness[23] and the retinal diseases Age-Related Macular Degeneration[24] and Macular telangiectasia.[25]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000163817 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000036814 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Nash SR, Giros B, Kingsmore SF, Kim KM, el-Mestikawy S, Dong Q, et al. (1998). "Cloning, gene structure and genomic localization of an orphan transporter from mouse kidney with six alternatively-spliced isoforms". Receptors & Channels. 6 (2): 113–28. PMID 9932288.
- ^ Kiss H, Kedra D, Kiss C, Kost-Alimova M, Yang Y, Klein G, et al. (April 2001). "The LZTFL1 gene is a part of a transcriptional map covering 250 kb within the common eliminated region 1 (C3CER1) in 3p21.3". Genomics. 73 (1): 10–9. doi:10.1006/geno.2000.6498. PMID 11352561.
- ^ Takanaga, Hitomi; Mackenzie, Bryan; Suzuki, Yoshiro; Hediger, Matthias A. (March 2005). "Identification of Mammalian Proline Transporter SIT1 (SLC6A20) with Characteristics of Classical System Imino". Journal of Biological Chemistry. 280 (10): 8974–8984. Bibcode:2005JBiCh.280.8974T. doi:10.1074/jbc.M413027200. PMID 15632147.
- ^ a b Bröer, Stefan; Gether, Ulrik (September 2012). "The solute carrier 6 family of transporters". British Journal of Pharmacology. 167 (2): 256–278. doi:10.1111/j.1476-5381.2012.01975.x. PMID 22519513.
- ^ a b Bröer, Angelika; Balkrishna, Sarojini; Kottra, Gabor; Davis, Sarah; Oakley, Aaron; Bröer, Stefan (January 2009). "Sodium translocation by the iminoglycinuria associated imino transporter (SLC6A20)". Molecular Membrane Biology. 26 (5–7): 333–346. doi:10.1080/09687680903150027. PMID 19657969.
- ^ Li, Huanyu Z.; Pike, Ashley C. W.; Lotsaris, Irina; Chi, Gamma; Hansen, Jesper S.; Lee, Sarah C.; Rödström, Karin E. J.; Bushell, Simon R.; Speedman, David; Evans, Adam; Wang, Dong; He, Didi; Shrestha, Leela; Nasrallah, Chady; Burgess-Brown, Nicola A.; Vandenberg, Robert J.; Dafforn, Timothy R.; Carpenter, Elisabeth P.; Sauer, David B. (29 June 2024). "Structure and function of the SIT1 proline transporter in complex with the COVID-19 receptor ACE2". Nature Communications. 15 (1) 5503. Bibcode:2024NatCo..15.5503L. doi:10.1038/s41467-024-48921-x. PMID 38951531.
- ^ Vuille-dit-Bille, Raphael N.; Camargo, Simone M.; Emmenegger, Luca; Sasse, Tom; Kummer, Eva; Jando, Julia; Hamie, Qeumars M.; Meier, Chantal F.; Hunziker, Schirin; Forras-Kaufmann, Zsofia; Kuyumcu, Sena; Fox, Mark; Schwizer, Werner; Fried, Michael; Lindenmeyer, Maja; Götze, Oliver; Verrey, François (April 2015). "Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors". Amino Acids. 47 (4): 693–705. doi:10.1007/s00726-014-1889-6. PMID 25534429.
- ^ Bröer S, Bailey CG, Kowalczuk S, Ng C, Vanslambrouck JM, Rodgers H, et al. (December 2008). "Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters". The Journal of Clinical Investigation. 118 (12): 3881–92. doi:10.1172/JCI36625. PMC 2579706. PMID 19033659.
- ^ Ellinghaus D, Degenhardt F, Bujanda L, Buti M, Albillos A, Invernizzi P, et al. (June 2020). "Genomewide Association Study of Severe Covid-19 with Respiratory Failure". The New England Journal of Medicine. 383 (16): 1522–1534. doi:10.1056/NEJMoa2020283. PMC 7315890. PMID 32558485.
- ^ Pairo-Castineira, Erola; Clohisey, Sara; Klaric, Lucija; Bretherick, Andrew D.; Rawlik, Konrad; Pasko, Dorota; Walker, Susan; Parkinson, Nick; Fourman, Max Head; Russell, Clark D.; Furniss, James; Richmond, Anne; Gountouna, Elvina; Wrobel, Nicola; Harrison, David; Wang, Bo; Wu, Yang; Meynert, Alison; Griffiths, Fiona; Oosthuyzen, Wilna; Kousathanas, Athanasios; Moutsianas, Loukas; Yang, Zhijian; Zhai, Ranran; Zheng, Chenqing; Grimes, Graeme; Beale, Rupert; Millar, Jonathan; Shih, Barbara; Keating, Sean; Zechner, Marie; Haley, Chris; Porteous, David J.; Hayward, Caroline; Yang, Jian; Knight, Julian; Summers, Charlotte; Shankar-Hari, Manu; Klenerman, Paul; Turtle, Lance; Ho, Antonia; Moore, Shona C.; Hinds, Charles; Horby, Peter; Nichol, Alistair; Maslove, David; Ling, Lowell; McAuley, Danny; Montgomery, Hugh; Walsh, Timothy; Pereira, Alexandre C.; Renieri, Alessandra; Shen, Xia; Ponting, Chris P.; Fawkes, Angie; Tenesa, Albert; Caulfield, Mark; Scott, Richard; Rowan, Kathy; Murphy, Lee; Openshaw, Peter J. M.; Semple, Malcolm G.; Law, Andrew; Vitart, Veronique; Wilson, James F.; Baillie, J. Kenneth (4 March 2021). "Genetic mechanisms of critical illness in COVID-19". Nature. 591 (7848): 92–98. doi:10.1038/s41586-020-03065-y. PMID 33307546.
- ^ COVID-19 Host Genetics, Initiative (December 2021). "Mapping the human genetic architecture of COVID-19". Nature. 600 (7889): 472–477. Bibcode:2021Natur.600..472C. doi:10.1038/s41586-021-03767-x. PMC 8674144. PMID 34237774.
{{cite journal}}: CS1 maint: numeric names: authors list (link) - ^ Shen, Yaping; Wang, Jianhui; Li, Yaning; Zhang, Yuanyuan; Tian, Ruilin; Yan, Renhong (16 November 2022). "Structures of ACE2–SIT1 recognized by Omicron variants of SARS-CoV-2". Cell Discovery. 8 (1) 123. doi:10.1038/s41421-022-00488-x. PMC 9667838. PMID 36384914.
- ^ Bae, Mihyun; Roh, Junyeop Daniel; Kim, Youjoung; Kim, Seong Soon; Han, Hye Min; Yang, Esther; Kang, Hyojin; Lee, Suho; Kim, Jin Yong; Kang, Ryeonghwa; Jung, Hwajin; Yoo, Taesun; Kim, Hyosang; Kim, Doyoun; Oh, Heejeong; Han, Sungwook; Kim, Dayeon; Han, Jinju; Bae, Yong Chul; Kim, Hyun; Ahn, Sunjoo; Chan, Andrew M; Lee, Daeyoup; Kim, Jin Woo; Kim, Eunjoon (5 February 2021). "SLC6A20 transporter: a novel regulator of brain glycine homeostasis and NMDAR function". EMBO Molecular Medicine. 13 (2) e12632. doi:10.15252/emmm.202012632. PMC 7863395. PMID 33428810.
- ^ Kim, Jeong-Hyun; Cheong, Hyun Sub; Sul, Jae Hoon; Seo, Jeong-Meen; Kim, Dae-Yeon; Oh, Jung-Tak; Park, Kwi-Won; Kim, Hyun-Young; Jung, Soo-Min; Jung, Kyuwhan; Cho, Min Jeng; Bae, Joon Seol; Shin, Hyoung Doo (13 October 2014). "A Genome-Wide Association Study Identifies Potential Susceptibility Loci for Hirschsprung Disease". PLOS ONE. 9 (10) e110292. Bibcode:2014PLoSO...9k0292K. doi:10.1371/journal.pone.0110292. PMC 4195606. PMID 25310821.
- ^ Lee, Jin Sol; Oh, Jung-Tak; Kim, Jeong-Hyun; Seo, Jeong-Meen; Kim, Dae-Yeon; Park, Kwi-Won; Kim, Hyun-Young; Jung, Kyuwhan; Park, Byung Lae; Koh, InSong; Shin, Hyoung Doo (January 2016). "Association Analysis of SLC6A20 Polymorphisms With Hirschsprung Disease". Journal of Pediatric Gastroenterology and Nutrition. 62 (1): 64–70. doi:10.1097/MPG.0000000000000880. PMID 26049783.
- ^ Xie, Xiaoli; He, Qiuming; Huang, Lihua; Li, Le; Yao, Yuxiao; Xia, Huimin; Zhao, Jinglu; Zhong, Wei; Zhang, Yan (30 August 2019). "Associations of SLC6A20 genetic polymorphisms with Hirschsprung's disease in a Southern Chinese population". Bioscience Reports. 39 (8) BSR20182290. doi:10.1042/BSR20182290. PMC 6692567. PMID 31358688.
- ^ Strunnikova, N.V.; Maminishkis, A.; Barb, J.J.; Wang, F.; Zhi, C.; Sergeev, Y.; Chen, W.; Edwards, A.O.; Stambolian, D.; Abecasis, G.; Swaroop, A.; Munson, P.J.; Miller, S.S. (15 June 2010). "Transcriptome analysis and molecular signature of human retinal pigment epithelium". Human Molecular Genetics. 19 (12): 2468–2486. doi:10.1093/hmg/ddq129. PMC 2876890. PMID 20360305.
- ^ Chao, JR; Knight, K; Engel, AL; Jankowski, C; Wang, Y; Manson, MA; Gu, H; Djukovic, D; Raftery, D; Hurley, JB; Du, J (4 August 2017). "Human retinal pigment epithelial cells prefer proline as a nutrient and transport metabolic intermediates to the retinal side". The Journal of Biological Chemistry. 292 (31): 12895–12905. doi:10.1074/jbc.M117.788422. PMC 5546030. PMID 28615447.
- ^ Gao, X Raymond; Huang, Hua; Kim, Heejin (1 April 2019). "Genome-wide association analyses identify 139 loci associated with macular thickness in the UK Biobank cohort". Human Molecular Genetics. 28 (7): 1162–1172. doi:10.1093/hmg/ddy422. PMC 6423416. PMID 30535121.
- ^ Bennis, Anna; Gorgels, Theo G. M. F.; ten Brink, Jacoline B.; van der Spek, Peter J.; Bossers, Koen; Heine, Vivi M.; Bergen, Arthur A. (30 October 2015). "Comparison of Mouse and Human Retinal Pigment Epithelium Gene Expression Profiles: Potential Implications for Age-Related Macular Degeneration". PLOS ONE. 10 (10) e0141597. Bibcode:2015PLoSO..1041597B. doi:10.1371/journal.pone.0141597. PMC 4627757. PMID 26517551.
- ^ Bonelli, Roberto; Jackson, Victoria E.; Prasad, Aravind; Munro, Jacob E.; Farashi, Samaneh; Heeren, Tjebo F. C.; Pontikos, Nikolas; Scheppke, Lea; Friedlander, Martin; Egan, Catherine A.; Allikmets, Rando; Ansell, Brendan R. E.; Bahlo, Melanie (2 March 2021). "Identification of genetic factors influencing metabolic dysregulation and retinal support for MacTel, a retinal disorder". Communications Biology. 4 (1) 274. doi:10.1038/s42003-021-01788-w. PMC 7925591. PMID 33654266.