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The endogenous CXXC motif governs the cadmium sensitivity of the renal Na+/glucose co-transporter.

Authors: Xia, X  Wang, G  Peng, Y  Tu, MG  Jen, J  Fang, H 
Citation: Xia X, etal., J Am Soc Nephrol. 2005 May;16(5):1257-65. Epub 2005 Apr 13.
Pubmed: (View Article at PubMed) PMID:15829715
DOI: Full-text: DOI:10.1681/ASN.2004070594

Cadmium (Cd2+) poisoning causes severe renal disorders manifested by defects in reabsorptive transport of various compounds. It is reported here that the renal brush-border membrane Na+/glucose co-transporter-1 (SGLT1) is a molecular target for Cd2+ toxicity. In micromolar concentrations, Cd2+ acted as a noncompetitive, partial inhibitor of methyl-D-glucopyranoside uptake in vesicles from COS-7 cells transiently expressing SGLT1. In contrast, only a modest effect in the closely related Na+/myo-inositol co-transporter-1 (SMIT1) was observed. The factor responsible for this difference was the CXXC motif (X can be any residue) at the cytoplasmic end of the eighth transmembrane segment (TM8) of SGLT1. Thus, a mutational transfer of this motif conveyed Cd2+ sensitivity to SMIT1. Moreover, mimicking the inhibitory effect of Cd2+, the biarsenical molecule FlAsH-EDT2 strongly inhibited the SGLT1 that had an engineered tetracysteine motif at the cytoplasmic end of TM8. The experiments also showed that covalent binding of the sulfhydryl reactive biotin-PEO-maleimide to the SGLT1 wild type but not to the mutant lacking the CXXC motif was suppressed by Cd2+. Taken together, these results suggest that in SGLT1, Cd2+ binding to the CXXC motif induces conformational changes that cause a partial inhibition of d-glucose transport.

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RGD ID: 1624261
Created: 2007-05-07
Species: All species
Last Modified: 2007-05-07
Status: ACTIVE



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