Skip Navigation


Human Molecular Genetics Advance Access originally published online on March 10, 2008
Human Molecular Genetics 2008 17(12):1845-1854; doi:10.1093/hmg/ddn080
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplementary Data
Right arrow All Versions of this Article:
17/12/1845    most recent
ddn080v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Bartoccioni, P.
Right arrow Articles by Chillarón, J.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bartoccioni, P.
Right arrow Articles by Chillarón, J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 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 Bartoccioni1,3,4, Mònica Rius1,2,3, Antonio Zorzano1,3, Manuel Palacín1,3,4,{dagger} and Josep Chillarón1,2,3,{dagger},*

1 Department of Biochemistry and Molecular Biology 2 Department of Animal Physiology, Faculty of Biology, University of Barcelona, Barcelona, Spain 3 Institute for Research in Biomedicine, Barcelona Science Park, Barcelona, Spain 4 CIBERER, Barcelona, Spain

* To whom correspondence should be addressed at: Department of Animal Physiology, Faculty of Biology, University of Barcelona, Av. Diagonal, 645, E-08028 Barcelona, Spain. Tel: +34 934034700/9385; Fax: +34 934110358; Email: jchillaron{at}ub.edu

Received December 20, 2007; 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.

{dagger} M.P. and J.C. share last authorship.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.