Biology:SLC6A20

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Solute carrier family 6, member 20 also known as SLC6A20 is a gene[1][2] that encodes for the Sodium/imino-acid transporter 1 (SIT1) protein, a plasma membrane proline and glycine transporter.[3]

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,[4] like other SLC6 amino acid and amine transporters, and a homolog of the Bacterial Leucine Transporter.[5]

Among the SLC6 transporters, only SIT1 and SLC6A7 (PROT) prefer secondary amino acids.[4] This selectivity arises due to the shape and highly conserved residues of the protein's binding site to exclude residues with extended site chains.[6]

Natively, SIT1 forms a complex with ACE2 or collectrin, which assists in trafficking the transporter to the plasma membrane.[7]

Clinical significance

Mutation in the SLC6A20 gene are associated with iminoglycinuria.[8][5]

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.[9][10][11] 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.[12]

SIT1 is proposed to modulate the activity of glycine and NMDA receptors,[13] and variants in the SLC6A20 gene are associated with Hirschprung's disease.[14][15][16]

SIT1 is also the primary proline transporter in the retinal pigment epithelium[17] and supports the proline-dependent metabolism of these cells.[18] Consequently, SLC6A20 gene variants are associated with retinal thickness[19] and the retinal diseases Age-Related Macular Degeneration[20] and Macular telangiectasia.[21]

References

  1. ↑ "Cloning, gene structure and genomic localization of an orphan transporter from mouse kidney with six alternatively-spliced isoforms". Receptors & Channels 6 (2): 113–28. 1998. PMID 9932288. 
  2. ↑ "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. April 2001. doi:10.1006/geno.2000.6498. PMID 11352561. 
  3. ↑ 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. doi:10.1074/jbc.M413027200. PMID 15632147. Bibcode: 2005JBiCh.280.8974T. 
  4. ↑ 4.0 4.1 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. 
  5. ↑ 5.0 5.1 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. 
  6. ↑ Li, Huanyu Z.; Pike, Ashley C. W.; Lotsaris, Irina; Chi, Gamma; Hansen, Jesper S.; Lee, Sarah C.; Rödström, Karin E. J.; Bushell, Simon R. et al. (29 June 2024). "Structure and function of the SIT1 proline transporter in complex with the COVID-19 receptor ACE2". Nature Communications 15 (1). doi:10.1038/s41467-024-48921-x. PMID 38951531. Bibcode: 2024NatCo..15.5503L. 
  7. ↑ Vuille-dit-Bille, Raphael N.; Camargo, Simone M.; Emmenegger, Luca; Sasse, Tom; Kummer, Eva; Jando, Julia; Hamie, Qeumars M.; Meier, Chantal F. et al. (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. 
  8. ↑ "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. December 2008. doi:10.1172/JCI36625. PMID 19033659. 
  9. ↑ "Genomewide Association Study of Severe Covid-19 with Respiratory Failure". The New England Journal of Medicine 383 (16): 1522–1534. June 2020. doi:10.1056/NEJMoa2020283. PMID 32558485. 
  10. ↑ Pairo-Castineira, Erola; Clohisey, Sara; Klaric, Lucija; Bretherick, Andrew D.; Rawlik, Konrad; Pasko, Dorota; Walker, Susan; Parkinson, Nick et al. (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. 
  11. ↑ COVID-19 Host Genetics, Initiative (December 2021). "Mapping the human genetic architecture of COVID-19.". Nature 600 (7889): 472–477. doi:10.1038/s41586-021-03767-x. PMID 34237774. Bibcode: 2021Natur.600..472C. 
  12. ↑ 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). doi:10.1038/s41421-022-00488-x. PMID 36384914. 
  13. ↑ Bae, Mihyun; Roh, Junyeop Daniel; Kim, Youjoung; Kim, Seong Soon; Han, Hye Min; Yang, Esther; Kang, Hyojin; Lee, Suho et al. (5 February 2021). "SLC6A20 transporter: a novel regulator of brain glycine homeostasis and NMDAR function". EMBO Molecular Medicine 13 (2). doi:10.15252/emmm.202012632. PMID 33428810. 
  14. ↑ Kim, Jeong-Hyun; Cheong, Hyun Sub; Sul, Jae Hoon; Seo, Jeong-Meen; Kim, Dae-Yeon; Oh, Jung-Tak; Park, Kwi-Won; Kim, Hyun-Young et al. (13 October 2014). "A Genome-Wide Association Study Identifies Potential Susceptibility Loci for Hirschsprung Disease". PLOS ONE 9 (10). doi:10.1371/journal.pone.0110292. PMID 25310821. Bibcode: 2014PLoSO...9k0292K. 
  15. ↑ Lee, Jin Sol; Oh, Jung-Tak; Kim, Jeong-Hyun; Seo, Jeong-Meen; Kim, Dae-Yeon; Park, Kwi-Won; Kim, Hyun-Young; Jung, Kyuwhan et al. (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. 
  16. ↑ Xie, Xiaoli; He, Qiuming; Huang, Lihua; Li, Le; Yao, Yuxiao; Xia, Huimin; Zhao, Jinglu; Zhong, Wei et al. (30 August 2019). "Associations of SLC6A20 genetic polymorphisms with Hirschsprung's disease in a Southern Chinese population". Bioscience Reports 39 (8). doi:10.1042/BSR20182290. PMID 31358688. 
  17. ↑ Strunnikova, N.V.; Maminishkis, A.; Barb, J.J.; Wang, F.; Zhi, C.; Sergeev, Y.; Chen, W.; Edwards, A.O. et al. (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. PMID 20360305. 
  18. ↑ Chao, JR; Knight, K; Engel, AL; Jankowski, C; Wang, Y; Manson, MA; Gu, H; Djukovic, D et al. (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. PMID 28615447. 
  19. ↑ 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. PMID 30535121. 
  20. ↑ 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). doi:10.1371/journal.pone.0141597. PMID 26517551. Bibcode: 2015PLoSO..1041597B. 
  21. ↑ Bonelli, Roberto; Jackson, Victoria E.; Prasad, Aravind; Munro, Jacob E.; Farashi, Samaneh; Heeren, Tjebo F. C.; Pontikos, Nikolas; Scheppke, Lea et al. (2 March 2021). "Identification of genetic factors influencing metabolic dysregulation and retinal support for MacTel, a retinal disorder". Communications Biology 4 (1). doi:10.1038/s42003-021-01788-w. PMID 33654266. 



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