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Novel cystine transporter in renal proximal tubule identified as a “missing partner” of cystinuria‐related membrane protein rBAT/SLC3A1
Author(s) -
Nagamori Shushi,
Wiriyasermkul Pattama,
Nakagomi Saya,
Okuyama Hirohisa,
Okuda Suguru,
Ohgaki Ryuichi Ohgaki,
Kanai Yoshikatsu
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb688
Subject(s) - cystinuria , cystine , aminoaciduria , reabsorption , chemistry , apical membrane , biochemistry , amino acid , amino acid transporter , fanconi syndrome , transporter , membrane , kidney , cysteine , biology , endocrinology , enzyme , gene
Heteromeric amino acid transporter (HAT) family is one of the major amino acid transporter families responsible for cellular uptake and epithelial transport. HATs form heterodimers composed of a 12 membrane spanning light chain (SLC7) that catalyzes transport functions and a single membrane spanning heavy chain (SLC3) essential for plasma membrane localization and stabilization of the light chains. Among HAT family, the heterodimer of b 0,+ AT/SLC7A9 and its auxiliary subunit rBAT/SLC3A1 is responsible for cystine reabsorption in renal proximal tubules. The mutations in either subunits cause cystinuria, an inherited aminoaciduria with impaired renal reabsorption of cystine and dibasic amino acids. However, an unsolved paradox is that rBAT is highly expressed in S3 segment, the late proximal tubules, whereas b 0,+ AT expression is the highest in S1 segment, the early proximal tubules. Therefore, the presence of unknown partner of rBAT in S3 segment has been proposed. In this study, by means of co‐immunoprecipitation followed by mass spectrometry, we have found that AGT1/SLC7A13 is the missing partner of rBAT. AGT1 is localized in the apical membrane of S3 segment, where it forms a heterodimer with rBAT. Proteoliposomes reconstituted purified AGT1‐rBAT heterodimer transported cystine, aspartate and glutamate. In the apical membrane of the S3 segment, AGT1 is suggested to locate itself in close proximity to sodium‐dependent acidic amino acid transporter EAAC1 for efficient functional coupling. EAAC1 is proposed to take up aspartate and glutamate released into luminal fluid by AGT1 due to its countertransport so that preventing the urinary loss of aspartate and glutamate. Taken all together, AGT1 is the long‐postulated second cystine transporter in S3 segment of proximal tubules and a candidate to be involved in isolated cystinuria. Support or Funding Information This work was supported in part by Grants‐in‐Aid for Scientific Research on Priority Areas of “Transportsome” (to Y.K.) and Innovative Areas “HD Physiology” (to S. Nagamori) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Grants‐in‐Aid for Scientific Research (to Y.K. and S. Nagamori) from the Japan Society for the Promotion of Science.