7b00
Human LAT2-4F2hc complex in the apo-state
Structural highlights
FunctionLAT2_HUMAN Associates with SLC3A2 to form a functional heterodimeric complex that translocates small and large neutral amino acids with broad specificity and a stoichiometry of 1:1. Functions as amino acid antiporter mediating the influx of extracellular essential amino acids mainly in exchange with the efflux of highly concentrated intracellular amino acids (PubMed:10391915, PubMed:11311135, PubMed:11847106, PubMed:12716892, PubMed:15081149, PubMed:15918515, PubMed:29355479, PubMed:33298890, PubMed:34848541). Has relatively symmetrical selectivities but strongly asymmetrical substrate affinities at both the intracellular and extracellular sides of the transporter (PubMed:11847106). This asymmetry allows SLC7A8 to regulate intracellular amino acid pools (mM concentrations) by exchange with external amino acids (uM concentration range), equilibrating the relative concentrations of different amino acids across the plasma membrane instead of mediating their net uptake (PubMed:10391915, PubMed:11847106). May play an essential role in the reabsorption of neutral amino acids from the epithelial cells to the bloodstream in the kidney (PubMed:12716892). 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 (PubMed:12117417). Involved in the cellular activity of small molecular weight nitrosothiols, via the stereoselective transport of L-nitrosocysteine (L-CNSO) across the transmembrane (PubMed:15769744). Imports the thyroid hormone diiodothyronine (T2) and to a smaller extent triiodothyronine (T3) but not rT 3 or thyroxine (T4) (By similarity). Mediates the uptake of L-DOPA (By similarity). May participate in auditory function (By similarity).[UniProtKB:Q9QXW9][UniProtKB:Q9WVR6][1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] Publication Abstract from PubMedDespite having similar structures, each member of the heteromeric amino acid transporter (HAT) family shows exquisite preference for the exchange of certain amino acids. Substrate specificity determines the physiological function of each HAT and their role in human diseases. However, HAT transport preference for some amino acids over others is not yet fully understood. Using cryo-electron microscopy of apo human LAT2/CD98hc and a multidisciplinary approach, we elucidate key molecular determinants governing neutral amino acid specificity in HATs. A few residues in the substrate-binding pocket determine substrate preference. Here, we describe mutations that interconvert the substrate profiles of LAT2/CD98hc, LAT1/CD98hc, and Asc1/CD98hc. In addition, a region far from the substrate-binding pocket critically influences the conformation of the substrate-binding site and substrate preference. This region accumulates mutations that alter substrate specificity and cause hearing loss and cataracts. Here, we uncover molecular mechanisms governing substrate specificity within the HAT family of neutral amino acid transporters and provide the structural bases for mutations in LAT2/CD98hc that alter substrate specificity and that are associated with several pathologies. Structural basis for substrate specificity of heteromeric transporters of neutral amino acids.,Rodriguez CF, Escudero-Bravo P, Diaz L, Bartoccioni P, Garcia-Martin C, Gilabert JG, Boskovic J, Guallar V, Errasti-Murugarren E, Llorca O, Palacin M Proc Natl Acad Sci U S A. 2021 Dec 7;118(49):e2113573118. doi: , 10.1073/pnas.2113573118. PMID:34848541[12] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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