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PMID:18701462
| Citation |
Feng, S, Okenka, GM, Bai, CX, Streets, AJ, Newby, LJ, DeChant, BT, Tsiokas, L, Obara, T and Ong, AC (2008) Identification and functional characterization of an N-terminal oligomerization domain for polycystin-2. J. Biol. Chem. 283:28471-9 |
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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. |
| Links |
PubMed PMC2568912 Online version:10.1074/jbc.M803834200 |
| Keywords |
Animals; Dimerization; Electrophysiology/methods; Humans; Immunohistochemistry/methods; Models, Biological; Mutation; Plasmids/metabolism; Polycystic Kidney Diseases/metabolism; Protein Binding; Protein Conformation; Protein Structure, Tertiary; TRPP Cation Channels/chemistry; TRPP Cation Channels/metabolism; Two-Hybrid System Techniques; Zebrafish |
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