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A single amino acid residue constitutes the third (...)

J Biol Chem. 2011 Apr ; [Epub ahead of print]
A single amino acid residue constitutes the third dimerization domain essential for the assembly and function of the tetrameric polycystin-2 (TRPP2) channel.
Feng S, Rodat-Despoix L, Delmas P, Ong AC.

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 similar to other TRP channels, it may form functional homo- or heterotetramers with other TRP subunits. We have recently demonstrated that the homodimerization of PC2 is mediated by both N-terminal and C-terminal domains and it is known that PC2 can heterodimerise with PC1, TRPC1 and TRPV4. In this paper, we report that a single cysteine residue, C632, mutated in a known PKD2 pedigree, constitutes the third dimerisation domain for PC2. PC2 truncation mutants lacking both N- and C-termini could still dimerise under non-reducing conditions. Mutation of C632 alone abolished dimerisation in these mutants, indicating that it was the critical residue mediating disulphide-bond formation between PC2 monomers. Co-expression of C632A PC2 mutants with wild-type PC2 channels reduced ATP-sensitive ER Ca2+ release in HEK293. The combination of C632A and mutations disrupting the C-terminal coiled coil domain (V846, I853, I860, L867 or 4M) nearly abolished dimer formation and ATP-dependent Ca2+ release. However, unlike the 4M PC2 mutant, a C632A mutant could still heterodimerise with polycystin-1 (PC1). Our results indicate that PC2 homodimerisation is regulated by three distinct domains and that these events regulate formation of the tetrameric PC2 channel.


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