Structure of the human PKD1-PKD2 complex

Abstract

Mutations in two genes, and, account for most cases of autosomal dominant polycystic kidney disease, one of the most common monogenetic disorders. Here we report the 3.6-angstrom cryo-electron microscopy structure of truncated human PKD1-PKD2 complex assembled in a 1:3 ratio. PKD1 contains a voltage-gated ion channel (VGIC) fold that interacts with PKD2 to form the domain-swapped, yet noncanonical, transient receptor potential (TRP) channel architecture. The S6 helix in PKD1 is broken in the middle, with the extracellular half, S6a, resembling pore helix 1 in a typical TRP channel. Three positively charged, cavity-facing residues on S6b may block cation permeation. In addition to the VGIC, a five-transmembrane helix domain and a cytosolic PLAT domain were resolved in PKD1. The PKD1-PKD2 complex structure establishes a framework for dissecting the function and disease mechanisms of the PKD proteins.

The ion channel function of polycystin‐1 in the polycystin‐1/polycystin‐2 complex

“…Second, our biochemical and biophysical studies found that the PC1/PC2 complex contains one PC1 and three PC2 subunits [39,40]. Fourth, the recently published cryo-EM structure of a transmembrane fraction of the human PC1/PC2 complex confirmed that this complex indeed has 1 (PC1): 3 (PC2) stoichiometry [42]. Third, our previous study showed that another PKD/TRPP complex, PKD1L3/TRPP3, shares the same 1:3 subunit stoichiometry and that the single PKD1L3 subunit functions as a channel-forming component [41].…”

“…When in complex with PC1, it is possible that either the F604P-induced S6 conformational changes are somehow blocked by the PC1 subunit, or the PC1 subunit directly clogs the pore, resulting in a smaller conductance of PC1/PC2_F604P in comparison with homomeric PC2_F604P (Fig EV1). Indeed, in the cryo-EM structure of PC1/PC2 [42], there is no bulky side chain from the Structure of the PC1/PC2 complex showing the side view of S10-S11 from the PC1 subunit and S5-S6 from one PC2 subunit in the cryo-EM structure of PC1/PC2 (PDB code 6A70) [42]. Thus, PC2_AA is distinct from PC2_F604P with respect to the way by which the channel pore is opened.…”

“…Oocyte numbers are indicated in parentheses. Indeed, the cryo-EM structure of PC1/PC2 indicates that the PC1 S6-S11 assemble with three PC2 proteins into a TRP channel-like structure [42]. : not significant, ***P < 0.001, Student's t-test).…”

“…Based on the cryo-EM structures of PC2 and PC1/PC2 complex [20,42], we selected several amino acids at the pore regions of both PC1 and PC2, and tested how mutations at these sites affect ion selectivity (Fig 6A). Based on the cryo-EM structures of PC2 and PC1/PC2 complex [20,42], we selected several amino acids at the pore regions of both PC1 and PC2, and tested how mutations at these sites affect ion selectivity (Fig 6A).…”

“…This complex shares overall structural similarity to the homotetrameric PC2 channel, with the last two transmembrane domains (S10-S11) of PC1 directly participating in forming the presumed channel pore [42]. This complex shares overall structural similarity to the homotetrameric PC2 channel, with the last two transmembrane domains (S10-S11) of PC1 directly participating in forming the presumed channel pore [42].…”