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Identification and functional characterization of an N-terminal oligomerization domain for polycystin-2*

Feng, S., Okenka, G.M., Bai, C.X., Streets, A.J., Newby, L.J., DeChant, B.T., Tsiokas, L., Obara, T. and Ong, A.C.M. (2008) Identification and functional characterization of an N-terminal oligomerization domain for polycystin-2*. Journal of Biological Chemistry, 283 (42). pp. 28471-28479. ISSN 0021-9258

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Abstract

Autosomal dominant polycystic kidney disease (ADPKD), the most common inherited cause of kidney failure, is caused by mutations in either PKD1 (85%) or PKD2 (15%). The PKD2 protein, polycystin-2 (PC2 or TRPP2), is a member of the transient receptor potential (TRP) superfamily and functions as a non-selective calcium channel. PC2 has been found to form oligomers in native tissues suggesting that it may form functional homo- or heterotetramers with other subunits, similar to other TRP channels. Our experiments unexpectedly revealed that PC2 mutant proteins lacking the known C-terminal dimerization domain were still able to form oligomers and co-immunoprecipitate full-length PC2, implying the possible existence of a proximal dimerization domain. Using yeast two-hybrid and biochemical assays, we have mapped an alternative dimerization domain to the N terminus of PC2 (NT2-1-223, L224X). Functional characterization of this domain demonstrated that it was sufficient to induce cyst formation in zebrafish embryos and inhibit PC2 surface currents in mIMCD3 cells probably by a dominant-negative mechanism. In summary, we propose a model for PC2 assembly as a functional tetramer which depends on both C- and N-terminal dimerization domains. These results have significant implications for our understanding of PC2 function and disease pathogenesis in ADPKD and provide a new strategy for studying PC2 function.

Item Type: Article
Copyright, Publisher and Additional Information: © 2008 American Society for Biochemistry and Molecular Biology. Reproduced according to the creative commons license.
Institution: The University of Sheffield
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine (Sheffield) > Clinical Sciences Division North (Sheffield) > Sheffield Kidney Institute
Depositing User: Miss Anthea Tucker
Date Deposited: 11 Aug 2009 08:56
Last Modified: 10 Jun 2014 22:05
Published Version: http://dx.doi.org/10.1074/jbc.M803834200
Status: Published
Publisher: American Society for Biochemistry and Molecular Biology
Refereed: Yes
Identification Number: 10.1074/jbc.M803834200
URI: http://eprints.whiterose.ac.uk/id/eprint/9068

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