Polycystin-2 Induces a Conformational Change in Polycystin-1

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in the genes encoding either polycystin-1 (PC1) or polycystin-2 (PC2). PC2 acts as a nonselective cation channel and together with PC1 plays a role in intracellular Ca(2+) signaling. Using atomic force microscopy (AFM) imaging, we have shown previously that the N and C termini of PC1 appear as unequally sized particles connected by a "string" largely composed of tandem immunoglobulin-like, polycystic kidney disease (PKD) domains. Here, we show that coexpression of PC1 and PC2 causes an elongation of the PC1 string and a corresponding reduction in the size of the larger (C-terminal) particle. This change in the conformation of PC1 does not depend on its delivery to the plasma membrane. In addition, the use of the L3040H PC1 mutant showed that the conformational change does not require GPS cleavage. Coexpression of PC1 with PC2 mutants revealed that the conformational change in PC1 does not require either a stable interaction between PC1 and PC2 or PC2 channel function. Finally, we show that the tandem PKD repeats and to a lesser extent the receptor for egg jelly (REJ) domain both contribute to the extension of the PC1 string in the presence of PC2. We propose that the PKD repeats detach from the C-terminal fragment in response to PC2 activity. The resulting remodeling of PC1 may be responsible for enhancing GPS cleavage of PC1 and the separation of the PC1 N-terminal fragment from the C terminus during its maturation.

Polycystin-1 maturation requires polycystin-2 in a dose-dependent manner

“…An additional study published after the submission of this manuscript also localized PC1-NTR to the PM (63), and suggested a PC1-NT product not tethered to PC1-CT. Our results suggest that the PC1-PC2 complex formation is required for ER exit of both proteins and imply that PC2 plays a role in folding/quality control of PC1. This is consistent with the observation that PC1 structure is altered upon PC2 binding (64). The major conclusion from this study is that PC2 acts as an important chaperone for PC1 maturation and localization.…”