| Structural highlights
Function
[LAT1_HUMAN] Sodium-independent, high-affinity transport of large neutral amino acids such as phenylalanine, tyrosine, leucine, arginine and tryptophan, when associated with SLC3A2/4F2hc. Involved in cellular amino acid uptake. Acts as an amino acid exchanger. Involved in the transport of L-DOPA across the blood-brain barrier, and that of thyroid hormones triiodothyronine (T3) and thyroxine (T4) across the cell membrane in tissues such as placenta. Plays a role in neuronal cell proliferation (neurogenesis) in brain. Involved in the uptake of methylmercury (MeHg) when administered as the L-cysteine or D,L-homocysteine complexes, and hence plays a role in metal ion homeostasis and toxicity. Involved in the cellular activity of small molecular weight nitrosothiols, via the stereoselective transport of L-nitrosocysteine (L-CNSO) across the transmembrane. May play an important role in high-grade gliomas. Mediates blood-to-retina L-leucine transport across the inner blood-retinal barrier which in turn may play a key role in maintaining large neutral amino acids as well as neurotransmitters in the neural retina. Acts as the major transporter of tyrosine in fibroblasts. When associated with LAPTM4B, recruits SLC3A2 and SLC7A5 to lysosomes to promote leucine uptake into these organelles and is required for mTORC1 activation (PubMed:25998567).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]
Publication Abstract from PubMed
The L-type amino acid transporter 1 (LAT1; also known as SLC7A5) catalyses the cross-membrane flux of large neutral amino acids in a sodium- and pH-independent manner(1-3). LAT1, an antiporter of the amino acid-polyamine-organocation superfamily, also catalyses the permeation of thyroid hormones, pharmaceutical drugs, and hormone precursors such as L-3,4-dihydroxyphenylalanine across membranes(2-6). Overexpression of LAT1 has been observed in a wide range of tumour cells, and it is thus a potential target for anti-cancer drugs(7-11). LAT1 forms a heteromeric amino acid transporter complex with 4F2 cell-surface antigen heavy chain (4F2hc; also known as SLC3A2)-a type II membrane glycoprotein that is essential for the stability of LAT1 and for its localization to the plasma membrane(8,9). Despite extensive cell-based characterization of the LAT1-4F2hc complex and structural determination of its homologues in bacteria, the interactions between LAT1 and 4F2hc and the working mechanism of the complex remain largely unknown(12-19). Here we report the cryo-electron microscopy structures of human LAT1-4F2hc alone and in complex with the inhibitor 2-amino-2-norbornanecarboxylic acid at resolutions of 3.3 A and 3.5 A, respectively. LAT1 exhibits an inward open conformation. Besides a disulfide bond association, LAT1 also interacts extensively with 4F2hc on the extracellular side, within the membrane, and on the intracellular side. Biochemical analysis reveals that 4F2hc is essential for the transport activity of the complex. Together, our characterizations shed light on the architecture of the LAT1-4F2hc complex, and provide insights into its function and the mechanisms through which it might be associated with disease.
Structure of the human LAT1-4F2hc heteromeric amino acid transporter complex.,Yan R, Zhao X, Lei J, Zhou Q Nature. 2019 Mar 13. pii: 10.1038/s41586-019-1011-z. doi:, 10.1038/s41586-019-1011-z. PMID:30867591[16]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Prasad PD, Wang H, Huang W, Kekuda R, Rajan DP, Leibach FH, Ganapathy V. Human LAT1, a subunit of system L amino acid transporter: molecular cloning and transport function. Biochem Biophys Res Commun. 1999 Feb 16;255(2):283-8. doi:, 10.1006/bbrc.1999.0206. PMID:10049700 doi:https://dx.doi.org/10.1006/bbrc.1999.0206
- ↑ Pineda M, Fernandez E, Torrents D, Estevez R, Lopez C, Camps M, Lloberas J, Zorzano A, Palacin M. Identification of a membrane protein, LAT-2, that Co-expresses with 4F2 heavy chain, an L-type amino acid transport activity with broad specificity for small and large zwitterionic amino acids. J Biol Chem. 1999 Jul 9;274(28):19738-44. PMID:10391915
- ↑ Rossier G, Meier C, Bauch C, Summa V, Sordat B, Verrey F, Kuhn LC. LAT2, a new basolateral 4F2hc/CD98-associated amino acid transporter of kidney and intestine. J Biol Chem. 1999 Dec 3;274(49):34948-54. PMID:10574970
- ↑ Broer A, Friedrich B, Wagner CA, Fillon S, Ganapathy V, Lang F, Broer S. Association of 4F2hc with light chains LAT1, LAT2 or y+LAT2 requires different domains. Biochem J. 2001 May 1;355(Pt 3):725-31. PMID:11311135
- ↑ Ritchie JW, Taylor PM. Role of the System L permease LAT1 in amino acid and iodothyronine transport in placenta. Biochem J. 2001 Jun 15;356(Pt 3):719-25. PMID:11389679
- ↑ Yanagida O, Kanai Y, Chairoungdua A, Kim DK, Segawa H, Nii T, Cha SH, Matsuo H, Fukushima J, Fukasawa Y, Tani Y, Taketani Y, Uchino H, Kim JY, Inatomi J, Okayasu I, Miyamoto K, Takeda E, Goya T, Endou H. Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. Biochim Biophys Acta. 2001 Oct 1;1514(2):291-302. PMID:11557028
- ↑ Friesema EC, Docter R, Moerings EP, Verrey F, Krenning EP, Hennemann G, Visser TJ. Thyroid hormone transport by the heterodimeric human system L amino acid transporter. Endocrinology. 2001 Oct;142(10):4339-48. PMID:11564694
- ↑ Okamoto Y, Sakata M, Ogura K, Yamamoto T, Yamaguchi M, Tasaka K, Kurachi H, Tsurudome M, Murata Y. Expression and regulation of 4F2hc and hLAT1 in human trophoblasts. Am J Physiol Cell Physiol. 2002 Jan;282(1):C196-204. PMID:11742812
- ↑ Simmons-Willis TA, Koh AS, Clarkson TW, Ballatori N. Transport of a neurotoxicant by molecular mimicry: the methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2. Biochem J. 2002 Oct 1;367(Pt 1):239-46. PMID:12117417 doi:https://dx.doi.org/10.1042/BJ20020841
- ↑ Kim DK, Kanai Y, Choi HW, Tangtrongsup S, Chairoungdua A, Babu E, Tachampa K, Anzai N, Iribe Y, Endou H. Characterization of the system L amino acid transporter in T24 human bladder carcinoma cells. Biochim Biophys Acta. 2002 Sep 20;1565(1):112-21. PMID:12225859
- ↑ Li S, Whorton AR. Identification of stereoselective transporters for S-nitroso-L-cysteine: role of LAT1 and LAT2 in biological activity of S-nitrosothiols. J Biol Chem. 2005 May 20;280(20):20102-10. Epub 2005 Mar 15. PMID:15769744 doi:https://dx.doi.org/10.1074/jbc.M413164200
- ↑ Nawashiro H, Otani N, Shinomiya N, Fukui S, Ooigawa H, Shima K, Matsuo H, Kanai Y, Endou H. L-type amino acid transporter 1 as a potential molecular target in human astrocytic tumors. Int J Cancer. 2006 Aug 1;119(3):484-92. doi: 10.1002/ijc.21866. PMID:16496379 doi:https://dx.doi.org/10.1002/ijc.21866
- ↑ Vumma R, Wiesel FA, Flyckt L, Bjerkenstedt L, Venizelos N. Functional characterization of tyrosine transport in fibroblast cells from healthy controls. Neurosci Lett. 2008 Mar 21;434(1):56-60. doi: 10.1016/j.neulet.2008.01.028. Epub , 2008 Jan 17. PMID:18262359 doi:https://dx.doi.org/10.1016/j.neulet.2008.01.028
- ↑ Milkereit R, Persaud A, Vanoaica L, Guetg A, Verrey F, Rotin D. LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation. Nat Commun. 2015 May 22;6:7250. doi: 10.1038/ncomms8250. PMID:25998567 doi:https://dx.doi.org/10.1038/ncomms8250
- ↑ Mastroberardino L, Spindler B, Pfeiffer R, Skelly PJ, Loffing J, Shoemaker CB, Verrey F. Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family. Nature. 1998 Sep 17;395(6699):288-91. PMID:9751058 doi:https://dx.doi.org/10.1038/26246
- ↑ Yan R, Zhao X, Lei J, Zhou Q. Structure of the human LAT1-4F2hc heteromeric amino acid transporter complex. Nature. 2019 Mar 13. pii: 10.1038/s41586-019-1011-z. doi:, 10.1038/s41586-019-1011-z. PMID:30867591 doi:https://dx.doi.org/10.1038/s41586-019-1011-z
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