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Articles in PresS, published online ahead of print March 18, 2002
Am J Physiol Renal Physiol, 10.1152/ajprenal.00071.2002
Submitted on February 19, 2002
Accepted on March 11, 2002
1 Departament de Bioquimica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
2 Departament de Bioanalisi Medica, IDIBAPS, IIBB-CSIC, Barcelona, Spain
3 Servei de Nefrologia, Institut d'Urologia, Nefrologia i Andrologia, Fundacio Puigvert, Barcelona, Spain
* To whom correspondence should be addressed. E-mail: chillaro{at}worldonline.es.
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 Blots from mouse and human kidney brush border membranes showed that rBAT and b0,+AT were solely expressed as heterodimers of identical size, and both proteins coprecipitated. Moreover, quantitative immunopurification of b0,+AT followed by SDS-PAGE and mass spectrometry analysis stablished 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 over b0,+AT protein in the kidney. Indeed, complete immunodepletion of b0,+AT did not coprecipitate more than 20-30 % of rBAT. Therefore, another rBAT-associated subunit may be present in latter parts of the proximal tubule.
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