9kju

Local refinement of the y+LAT1-4F2hc bound with Arg

spinqualitylabelsall models 9kju, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9kju is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.7Å Ligands: ARG, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function 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. Publication Abstract from PubMed Heteromeric amino acid transporters (HATs), including y(+)LAT1-4F2hc complex, are responsible for transporting amino acids across membranes, and mutations in y(+)LAT1 cause lysinuric protein intolerance (LPI), a hereditary disorder characterized by defective cationic amino acid transport. The relationship between LPI and specific mutations in y(+)LAT1 has yet to be fully understood. In this study, we characterized the function of y(+)LAT1-4F2hc complex in mammalian cells and determined the cryo-EM structures of the human y(+)LAT1-4F2hc complex in two distinct conformations: the apo state in an inward-open conformation and the native substrate-bound state in an outward-open conformation. Structural analysis suggests that Asp(243) in y(+)LAT1 plays a crucial role in coordination with sodium ion and substrate selectivity. Molecular dynamic (MD) simulations further revealed the different transport mechanism of cationic amino acids and neutral amino acids. These results provide important insights into the mechanisms of the substrate binding and working cycle of HATs. Structural basis for the substrate recognition and transport mechanism of the human y(+)LAT1-4F2hc transporter complex.,Dai L, Zeng Q, Zhang T, Zhang Y, Shi Y, Li Y, Xu K, Huang J, Wang Z, Zhou Q, Yan R Sci Adv. 2025 Mar 21;11(12):eadq0558. doi: 10.1126/sciadv.adq0558. Epub 2025 Mar , 19. PMID:40106545 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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