Structure and function of polycystins: insights into polycystic kidney disease.

Dominique Douguet,Eric Honoré,Amanda Patel

doi:10.1038/s41581-019-0143-6

Abstract

Mutations in the polycystins PC1 or PC2 cause autosomal dominant polycystic kidney disease (ADPKD), which is characterized by the formation of fluid-filled renal cysts that disrupt renal architecture and function, ultimately leading to kidney failure in the majority of patients. Although the genetic basis of ADPKD is now well established, the physiological function of polycystins remains obscure and a matter of intense debate. The structural determination of both the homomeric PC2 and heteromeric PC1-PC2 complexes, as well as the electrophysiological characterization of PC2 in the primary cilium of renal epithelial cells, provided new valuable insights into the mechanisms of ADPKD pathogenesis. Current findings indicate that PC2 can function independently of PC1 in the primary cilium of renal collecting duct epithelial cells to form a channel that is mainly permeant to monovalent cations and is activated by both membrane depolarization and an increase in intraciliary calcium. In addition, PC2 functions as a calcium-activated calcium release channel at the endoplasmic reticulum membrane. Structural studies indicate that the heteromeric PC1-PC2 complex comprises one PC1 and three PC2 channel subunits. Surprisingly, several positively charged residues from PC1 occlude the ionic pore of the PC1-PC2 complex, suggesting that pathogenic polycystin mutations might cause ADPKD independently of an effect on channel permeation. Emerging reports of novel structural and functional findings on polycystins will continue to elucidate the molecular basis of ADPKD.

Highlights

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common human monogenic diseases, with a prevalence of about 1 in 1000 1,2
Mutations that cause ADPKD occur on PKD1 and PKD2, which encode polycystin 1 (PC1; known as PKD1) and polycystin 2 (PC2; known as PKD2 or TRPP2), respectively 5,6
Three positively-charged residues from the S6 – Arg4100, Arg4107 and His4111 –face the conduction pathway and are predicted to prevent cation permeation through the pore (FIG. 1e). These findings suggest that the heteromeric PC1–PC2 complex may be non-conductive and that PC1 could act as a dominant-negative subunit of the PC2 channel 33

Summary

Introduction

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common human monogenic diseases, with a prevalence of about 1 in 1000 1,2. Those data suggested that PC2 can function independently of PC1 as a cationic channel with low calcium permeability; this function seems to be restricted to the primary cilium [G] and is not observed in other areas of the plasma membrane.

Results

Conclusion