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1 Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona 08028, 2 Departament de Bioanàlisi Mèdica, Institut d'Investigaciones Biomédiques Pi y Sunyer, Insituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas, Barcelona 08036; and 3 Servei de Nefrologia Institut d'Urologia, Nefrologia i Andrologia, Fundació Puigvert, Barcelona 08025, Spain
Mutations in the rBAT and b0,+AT genes cause type I and non-type I cystinuria, respectively. The disulfide-linked rBAT-b0,+AT heterodimer mediates high-affinity transport of cystine and dibasic amino acids (b0,+-like activity) in heterologous cell systems. However, the significance of this heterodimer for cystine reabsorption is unknown, as direct evidence for such a complex in vivo is lacking and the expression patterns of rBAT and b0,+AT along the proximal tubule are opposite. We addressed this issue by biochemical means. Western blot analysis of mouse and human kidney brush-border membranes showed that rBAT and b0,+AT were solely expressed as heterodimers of identical size and that both proteins coprecipitated. Moreover, quantitative immunopurification of b0,+AT followed by SDS-PAGE and mass spectrometry analysis established that b0,+AT heterodimerizes exclusively with rBAT. Together with cystine reabsorption data, our results demonstrate that a decreasing expression gradient of heterodimeric rBAT-b0,+AT along the proximal tubule is responsible for virtually all apical cystine reabsorption. As a corollary of the above, there should be an excess of rBAT expression over that of b0,+AT protein in the kidney. Indeed, complete immunodepletion of b0,+AT did not coprecipitate >20-30% of rBAT. Therefore, another rBAT-associated subunit may be present in latter parts of the proximal tubule.
proximal tubule; heterodimeric amino acid transporter; expression gradient
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