View source for 6irs


==human LAT1-4F2hc complex incubated with JPH203==
<SX load='6irs' size='340' side='right' viewer='molstar' caption='[[6irs]], [[Resolution|resolution]] 3.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6irs]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6IRS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6IRS FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3PH:1,2-DIACYL-GLYCEROL-3-SN-PHOSPHATE'>3PH</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6irs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6irs OCA], [https://pdbe.org/6irs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6irs RCSB], [https://www.ebi.ac.uk/pdbsum/6irs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6irs ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/4F2_HUMAN 4F2_HUMAN] Required for the function of light chain amino-acid transporters. Involved in sodium-independent, high-affinity transport of large neutral amino acids such as phenylalanine, tyrosine, leucine, arginine and tryptophan. Involved in guiding and targeting of LAT1 and LAT2 to the plasma membrane. When associated with SLC7A6 or SLC7A7 acts as an arginine/glutamine exchanger, following an antiport mechanism for amino acid transport, influencing arginine release in exchange for extracellular amino acids. Plays a role in nitric oxide synthesis in human umbilical vein endothelial cells (HUVECs) via transport of L-arginine. Required for normal and neoplastic cell growth. When associated with SLC7A5/LAT1, is also 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. 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. When associated with SLC7A5 or SLC7A8, involved in the cellular activity of small molecular weight nitrosothiols, via the stereoselective transport of L-nitrosocysteine (L-CNSO) across the transmembrane. Together with ICAM1, regulates the transport activity LAT2 in polarized intestinal cells, by generating and delivering intracellular signals. When associated with SLC7A5, plays an important role in transporting L-leucine from the circulating blood to the retina across the inner blood-retinal barrier.<ref>PMID:11557028</ref> <ref>PMID:9829974</ref> <ref>PMID:9751058</ref> <ref>PMID:9878049</ref> <ref>PMID:10903140</ref> <ref>PMID:11311135</ref> <ref>PMID:11389679</ref> <ref>PMID:11564694</ref> <ref>PMID:11742812</ref> <ref>PMID:12117417</ref> <ref>PMID:12225859</ref> <ref>PMID:14603368</ref> <ref>PMID:12716892</ref> <ref>PMID:15980244</ref> <ref>PMID:15769744</ref> 
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== 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<ref>PMID:30867591</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 6irs" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Lei JL]]
[[Category: Yan RH]]
[[Category: Zhao X]]
[[Category: Zhou Q]]