The ubiquitin-protein ligase nedd4-2 differentially interacts with and regulates Mmembers of the tweety family of chloride ion channels

He, Yaowu, Hryciw, Deanne H., Carroll, Melanie L., Myers, Stephen A., Whitbread, Astrid K., Kumar, Sharad, Poronnik, Philip, & Hooper, John D. (2008) The ubiquitin-protein ligase nedd4-2 differentially interacts with and regulates Mmembers of the tweety family of chloride ion channels. The Jounral of Biological Chemistry, 283(35), pp. 24000-24010.

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The Tweety proteins comprise a family of chloride ion channels with three members identified in humans (TTYH1-3) and orthologues in fly and murine species. In humans, increased TTYH2 expression is associated with cancer progression, whereas fly Tweety is associated with developmental processes. Structurally, Tweety proteins are characterized by five membrane-spanning domains and N-glycan modifications important for trafficking to the plasma membrane, where these proteins are oriented with the amino terminus located extracellularly and the carboxyl terminus cytoplasmically. In addition to N-glycosylation, ubiquitination mediated by the HECT type E3 ubiquitin ligase Nedd4-2 is a post-translation modification important in regulating membrane proteins. In the present study, we performed a comprehensive analysis of the ability of each of TTYH1-3 to interact with Nedd4-2 and to be ubiquitinated and regulated by this ligase. Our data indicate that Nedd4-2 binds to two family members, TTYH2 and TTYH3, which contain consensus PY ((L/P)PXY) binding sites for HECT type E3 ubiquitin ligases, but not to TTYH1, which lacks this motif. Consistently, Nedd4-2 ubiquitinates both TTYH2 and TTYH3. Importantly, we have shown that endogenous TTYH2 and Nedd4-2 are binding partners and demonstrated that the TTYH2 PY motif is essential for these interactions. We have also shown that Nedd4-2-mediated ubiquitination of TTYH2 is a critical regulator of cell surface and total cellular levels of this protein. These data, indicating that Nedd4-2 differentially interacts with and regulates TTYH1-3, will be important for understanding mechanisms controlling Tweety proteins in physiology and disease.

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17 citations in Web of Science®
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ID Code: 17352
Item Type: Journal Article
Refereed: Yes
Additional Information: For more information, please refer to the journal's website (see hypertext link) or contact the author.
Keywords: Ion channel, TTYH2, Kidney
DOI: 10.1074/jbc.M803361200
ISSN: 1083-351X 1 0021-9258
Subjects: Australian and New Zealand Standard Research Classification > BIOLOGICAL SCIENCES (060000) > BIOCHEMISTRY AND CELL BIOLOGY (060100) > Receptors and Membrane Biology (060110)
Divisions: Past > QUT Faculties & Divisions > Faculty of Science and Technology
Current > Institutes > Institute of Health and Biomedical Innovation
Past > Schools > School of Life Sciences
Copyright Owner: Copyright 2008 The American Society for Biochemistry and Molecular Biology, Inc.
Deposited On: 04 Feb 2009 00:09
Last Modified: 09 Apr 2014 12:21

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