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Published VersionCC BY V4.0, Open Access
Published VersionCC BY V4.0, Open
Journal article
The ubiquitin-protein ligase Nedd4-2 differentially interacts with and regulates members of the Tweety family of chloride ion channels
Journal of Biological Chemistry, Vol.283(35), pp.24000-24010
2008
PMCID: PMC3259790
PMID: 18577513
Abstract
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 membranespanning 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 TTYH2PY 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.
Details
- Title
- The ubiquitin-protein ligase Nedd4-2 differentially interacts with and regulates members of the Tweety family of chloride ion channels
- Authors
- Yaowu He - Queensland University of TechnologyDeanne H. Hryciw - The University of QueenslandMelanie L. Carroll - Queensland University of TechnologyStephen A. Myers - Queensland University of TechnologyAstrid K. Whitbread - Queensland University of TechnologySharad Kumar - Queensland University of TechnologyPhilip Poronnik - The University of QueenslandJohn D. Hooper (Corresponding Author) - Queensland University of Technology
- Publication details
- Journal of Biological Chemistry, Vol.283(35), pp.24000-24010
- Publisher
- Elsevier Inc.
- Date published
- 2008
- DOI
- 10.1074/jbc.M803361200
- ISSN
- 1083-351X
- PMID
- 18577513; PMC3259790
- Copyright note
- This is an Open Access article under the CC BY license. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc
- Grant note
- This work was supported by National Health and Medical Research Council of Australia grants (to J. D. H., P. P., and S. K.) and a fellowship (to J. D. H.) and Australian Research Council grants (to P. P. and S. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Organisation Unit
- School of Health - Biomedicine
- Language
- English
- Record Identifier
- 991187229802621
- Output Type
- Journal article
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