title: A y(+)LAT-1 mutant protein interferes with y(+)LAT-2 activity: implications for the molecular pathogenesis of lysinuric protein intolerance.
abstract: Lysinuric protein intolerance (LPI) is an inherited aminoaciduria caused by defective cationic amino acid (CAA) transport at the basolateral membrane of epithelial cells in the intestine and kidney. The SLC7A7 gene, mutated in LPI, encodes the y(+)LAT-1 protein, which is the light subunit of the heterodimeric CAA transporter in which 4F2hc is the heavy chain subunit. Co-expression of 4F2hc and y(+)LAT-1 induces the y(+)L activity. This activity is also exerted by another complex composed of 4F2hc and y(+)LAT-2, the latter encoded by the SLC7A6 gene and more ubiquitously expressed than SLC7A7. On the basis of both the pattern of expression and the transport activity, y(+)LAT-2 might compensate for CAA transport when y(+)LAT-1 is defective. By expression in Xenopus laevis oocytes and mammalian cells, we functionally analysed two SLC7A7 mutants, E36del and F152L, respectively, the former displaying a partial dominant-negative effect. The results of the present study provide further insight into the molecular pathogenesis of LPI: a putative multiheteromeric structure of both [4F2hc/y(+)LAT-1] and [4F2hc/y(+)LAT-2], and the interference between y(+)LAT-1 and y(+)LAT-2 proteins. This interference can explain why the compensatory mechanism, that is, an increased expression of SLC7A6 as seen in lymphoblasts from LPI patients, may not be sufficient to restore the y(+)L system activity.
authors.affiliation: Department of Pediatrics, Federico II University, Naples, Italy. mpsperandeo@dti.telethon.it
authors.forename: Maria P
authors.initials: MP
authors.lastname: Sperandeo
authors.forename: Simona
authors.initials: S
authors.lastname: Paladino
authors.forename: Luigi
authors.initials: L
authors.lastname: Maiuri
authors.forename: George D
authors.initials: GD
authors.lastname: Maroupulos
authors.forename: Chiara
authors.initials: C
authors.lastname: Zurzolo
authors.forename: Maurizio
authors.initials: M
authors.lastname: Taglialatela
authors.forename: Generoso
authors.initials: G
authors.lastname: Andria
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Sebastio
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics*; D027241:Amino Acid Transport System y+L; D026923:Amino Acid Transport Systems, Basic / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000378:metabolism; D002460:Cell Line; D002675:Child, Preschool; D004285:Dogs; D027301:Fusion Regulatory Protein 1, Light Chains / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000652:urine*; D008297:Male; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D027241:Amino Acid Transport System y+L; D026923:Amino Acid Transport Systems, Basic; D027301:Fusion Regulatory Protein 1, Light Chains; C469951:SLC7A6 protein, human; C421261:SLC7A7 protein, human; D001120:Arginine; D008239:Lysine