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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Fahlke, Christoph Wojciechowski, Daniel Fischer, Martin |
| Description | Author Affiliation: Wojciechowski D ( From the Institut für Neurophysiologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany and.); Fischer M ( From the Institut für Neurophysiologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany and.); Fahlke C ( Institute of Complex Systems-Zelluläre Biophysik (ICS-4), Forschungszentrum Jülich, 52428 Jülich Germany c.fahlke@fz-juelich.de.) |
| Abstract | CLC-K chloride channels are expressed in the kidney and in the inner ear and require the accessory subunit barttin for proper function and membrane insertion. Barttin exerts multiple functions on CLC-proteins: it modifies protein stability and intracellular trafficking as well as channel activity, ion conduction, and gating. So far, the molecular determinants of these distinct barttin functions have remained elusive. Here we performed serial perturbation mutagenesis to identify the sequence determinants of barttin function. Barttin consists of two transmembrane helices followed by a long intracellular carboxyl terminus, and earlier work demonstrated that the transmembrane core of barttin suffices for most effects on the -subunit. We individually substituted every amino acid of the predicted transmembrane core (amino acids 9-26 and 35-55) with tryptophan, co-expressed mutant barttin with hClC-Ka or V166E rClC-K1, and characterized CLC-K/barttin channels by patch clamp techniques, biochemistry, and confocal microscopy. The majority of mutations left the chaperone function of barttin, i.e. the effects on endoplasmic reticulum exit and surface membrane insertion, unaffected. In contrast, tryptophan insertion at multiple positions resulted in impaired activity of hClC-Ka/barttin and changes in gating of V166E rClC-K1/barttin. These results demonstrate that mutations in a cluster of hydrophobic residues within transmembrane domain 1 affect barttin-CLC-K interaction and impair gating modification by the accessory subunit. Whereas tight interaction is necessary for functional modification, even impaired association of barttin and CLC-K suffices for normal intracellular trafficking. Our findings allow definition of a likely interaction surface and clarify the mechanisms underlying CLC-K channel modification by barttin. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 30 |
| Volume Number | 290 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2015-07-24 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Chloride Channels Metabolism Kidney Physiology Tryptophan Animals Chemistry Genetics Cytoplasm Endoplasmic Reticulum HEK293 Cells Hydrophobic And Hydrophilic Interactions Microscopy, Confocal Mutagenesis, Site-Directed Mutation Patch-Clamp Techniques Research Support, Non-U.S. Gov't Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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