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An internalization signal in ClC-5, an endosomal Cl-channel mutated in dent's disease

Item Type:Article
Title:An internalization signal in ClC-5, an endosomal Cl-channel mutated in dent's disease
Creators Name:Schwake, M. and Friedrich, T. and Jentsch, T.J.
Abstract:The ClC-5 chloride channel resides mainly in vesicles of the endocytotic pathway and contributes to their acidification. Its disruption in mice entails a broad defect in renal endocytosis and causes secondary changes in calciotropic hormone levels. Inactivating mutations in Dent's disease lead to proteinuria and kidney stones. Possibly by recycling, a small fraction of ClC-5 also reaches the plasma membrane. Here we identify a carboxyl-terminal internalization motif in ClC-5. It resembles the PY motif, which is crucial for the endocytosis and degradation of epithelial Na(+) channels. Mutating this motif increases surface expression and currents about 2-fold. This is probably because of interactions with WW domains, because dominant negative mutants of the ubiquitin-protein ligase WWP2 increased surface expression and currents of ClC-5 only when its PY motif was intact. Stimulating endocytosis by expressing rab5 or its GTPase-deficient Q79L mutant decreased WT ClC-5 currents but did not affect channels with mutated motifs. Similarly, decreasing endocytosis by expressing the inactive S34N mutant of rab5 increased ClC-5 currents only if its PY-like motif was intact. Thus, the endocytosis of ClC-5, which itself is crucial for the endocytosis of other proteins, depends on the interaction of a carboxyl-terminal internalization signal with ubiquitin-protein ligases containing WW domains.
Keywords:Amino Acid Sequence, Chloride Channels, Endocytosis, Endosomes, Kidney Diseases, Molecular Sequence Data, Site-Directed Mutagenesis, Amino Acid Sequence Homology, Animals, Mice, Xenopus Laevis
Source:Journal of Biological Chemistry
ISSN:0021-9258
Publisher:American Society for Biochemistry and Molecular Biology (U.S.A.)
Volume:276
Number:15
Page Range:12049-12054
Date:13 April 2001
Official Publication:https://doi.org/10.1074/jbc.M010642200
PubMed:View item in PubMed

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