| Structural highlights
Disease
S6A20_HUMAN Iminoglycinuria. 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. Haploinsufficiency of SLC6A20 combined with deficiency of the neutral amino acid transporter SLC6A19 or partially inactivating mutations in SLC36A2, is responsible for iminoglycinuria. Additional polymorphisms and mutations in SLC6A18 can contribute to the IG phenotype in some families.
Function
S6A20_HUMAN Mediates the Na(+)- and Cl(-)-dependent uptake of imino acids such as L-proline, N-methyl-L-proline and pipecolate as well as N-methylated amino acids (PubMed:15632147, PubMed:19033659, PubMed:33428810). Also transports glycine, regulates proline and glycine homeostasis in the brain playing a role in the modulation of NMDAR currents (PubMed:33428810).[1] [2] [3]
Publication Abstract from PubMed
The pharmacology of amino acid transporters in the SLC6 family is poorly developed compared to that of the neurotransmitter transporters. To identify new inhibitors of the proline transporter SIT1 (SLC6A20), its expression in Xenopus laevis oocytes was optimized. Trafficking of SIT1 was augmented by co-expression of angiotensin-converting enzyme 2 (ACE2) in oocytes but there was no strict requirement for co-expression of ACE2. A pharmacophore-guided screen identified tiagabine as a potent non-competitive inhibitor of SIT1. To understand its binding mode, we determined the cryo-electron microscopy (cryo-EM) structure of ACE2-SIT1 bound with tiagabine. The inhibitor binds close to the orthosteric proline binding site, but due to its size extends into the cytosolic vestibule. This causes the transporter to adopt an inward-open conformation, in which the intracellular gate is blocked. This study provides the first structural insight into inhibition of SIT1 and generates tools for a better understanding of the ACE2-SIT1 complex. These findings may have significance for SARS-CoV-2 binding to its receptor ACE2 in human lung alveolar cells where SIT1 and ACE2 are functionally expressed.
Cryo-EM structure of ACE2-SIT1 in complex with tiagabine.,Broer A, Hu Z, Kukulowicz J, Yadav A, Zhang T, Dai L, Bajda M, Yan R, Broer S J Biol Chem. 2024 Aug 17;300(9):107687. doi: 10.1016/j.jbc.2024.107687. PMID:39159813[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Takanaga H, Mackenzie B, Suzuki Y, Hediger MA. Identification of mammalian proline transporter SIT1 (SLC6A20) with characteristics of classical system imino. J Biol Chem. 2005 Mar 11;280(10):8974-84. Epub 2005 Jan 4. PMID:15632147 doi:http://dx.doi.org/M413027200
- ↑ Broer S, Bailey CG, Kowalczuk S, Ng C, Vanslambrouck JM, Rodgers H, Auray-Blais C, Cavanaugh JA, Broer A, Rasko JE. Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters. J Clin Invest. 2008 Dec;118(12):3881-92. doi: 10.1172/JCI36625. Epub 2008 Nov 6. PMID:19033659 doi:http://dx.doi.org/10.1172/JCI36625
- ↑ Bae M, Roh JD, Kim Y, Kim SS, Han HM, Yang E, Kang H, Lee S, Kim JY, Kang R, Jung H, Yoo T, Kim H, Kim D, Oh H, Han S, Kim D, Han J, Bae YC, Kim H, Ahn S, Chan AM, Lee D, Kim JW, Kim E. SLC6A20 transporter: a novel regulator of brain glycine homeostasis and NMDAR function. EMBO Mol Med. 2021 Feb 5;13(2):e12632. doi: 10.15252/emmm.202012632. Epub 2021 , Jan 11. PMID:33428810 doi:http://dx.doi.org/10.15252/emmm.202012632
- ↑ Bröer A, Hu Z, Kukułowicz J, Yadav A, Zhang T, Dai L, Bajda M, Yan R, Bröer S. Cryo-EM structure of ACE2-SIT1 in complex with tiagabine. J Biol Chem. 2024 Aug 17;300(9):107687. PMID:39159813 doi:10.1016/j.jbc.2024.107687
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