Polycystin-2 induces a conformational change in polycystin-1

Area of Science:

• Molecular biology
• Cell biology
• Biophysics

Background:

• Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder caused by mutations in PC1 or PC2 genes.
• PC1 and PC2 proteins interact and are crucial for intracellular calcium signaling.
• Previous studies visualized PC1 termini connected by a string of PKD domains using AFM.

Purpose of the Study:

• To investigate the conformational changes in PC1 upon coexpression with PC2.
• To determine the role of PC2 interaction, GPS cleavage, and specific PC1 domains in PC1 remodeling.

Main Methods:

• Atomic force microscopy (AFM) imaging of PC1 and PC2 interactions.
• Coexpression of wild-type and mutant PC1 and PC2 proteins.
• Analysis of PC1 conformation, including string elongation and particle size changes.

Main Results:

• Coexpression of PC1 and PC2 elongated the PC1 string and reduced the C-terminal particle size.
• This conformational change occurred independently of plasma membrane delivery and GPS cleavage.
• PC2 mutants showed that stable interaction or channel function was not required for PC1 remodeling.
• PKD repeats and REJ domain of PC1 contribute to string extension with PC2.

Conclusions:

• PC2 activity induces PC1 remodeling, likely involving the detachment of PKD repeats from the C-terminal fragment.
• This remodeling may enhance PC1 maturation, including GPS cleavage and N- and C-terminal fragment separation.