|ZFIN ID: ZDB-PUB-080826-12|
Identification and functional characterisation of an N-terminal oligomerisation 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.
|Source:||The Journal of biological chemistry 283(42): 28471-28479 (Journal)|
|Registered Authors:||Obara, Tomoko|
|PubMed:||18701462 Full text @ J. Biol. Chem.|
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. (2008) Identification and functional characterisation of an N-terminal oligomerisation domain for polycystin-2. The Journal of biological chemistry. 283(42):28471-28479.
ABSTRACTAutosomal 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 dimerisation domain, were still able to form oligomers and co-immunoprecipitate full-length PC2, implying the possible existence of a proximal dimerisation domain. Using yeast two-hybrid and biochemical assays, we have mapped an alternative dimerisation domain to the N-terminus of PC2 (NT2 1-223, L224X). Functional characterisation 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 dimerisation 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.