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Human Molecular Genetics Advance Access published online on March 10, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn080
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Distinct classes of trafficking rBAT mutants cause the type I cystinuria phenotype

Paola Bartoccioni1,2, Mònica Rius1,3, Antonio Zorzano1, Manuel Palacín1,2,# and Josep Chillarón1,3,#,*

1 Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona and Institute for Research in Biomedicine, Barcelona Science Park, Barcelona, Spain 2 CIBERER, Barcelona, Spain 3 Department of Animal Physiology, Faculty of Biology, University of Barcelona, Spain

* Address correspondence to: Josep Chillarón, Dpt. of Animal Physiology, Faculty of Biology, University of Barcelona, Av. Diagonal, 645, E-08028, Barcelona, Spain Tel 34 934034700/9385; Fax 34 934110358; E-mail: jchillaron{at}ub.edu

Received December 20, 2007; Revised March 9, 2008; Accepted March 9, 2008

Most mutations in the rBAT subunit of the heterodimeric cystine transporter rBAT-b0,+AT cause type I cystinuria. Trafficking of the transporter requires the intracellular assembly of the two subunits. Without its partner, rBAT, but not b0,+AT, is rapidly degraded. We analyzed the initial biogenesis of wild type rBAT and type I cystinuria rBAT mutants. rBAT was degraded, at least in part, via the ERAD pathway. Assembly with b0,+AT within the endoplasmic reticulum (ER) blocked rBAT degradation and could be independent of the calnexin chaperone system. This system was, however, necessary for post-assembly maturation of the heterodimer. Without b0,+AT, wild type and rBAT mutants were degraded with similar kinetics. In its presence, rBAT mutants showed strongly reduced (L89P) or no transport activity, failed to acquire complex N-glycosylation and to oligomerize, suggesting assembly and/or folding defects. Most of the transmembrane domain mutant L89P did not heterodimerize with b0,+AT and was degraded. However, the few [L89P]rBAT-b0,+AT heterodimers were stable, consistent with assembly, but not folding, defects. Mutants of the rBAT extracellular domain (T216M, R365W, M467K and M467T) efficiently assembled with b0,+AT but were subsequently degraded. Together with earlier results, the data suggest a two-step biogenesis model, with the early assembly of the subunits followed by folding of the rBAT extracellular domain. Defects on either of these steps lead to the type I cystinuria phenotype.

# M.P. and J.C. share last authorship.


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