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Structure and function of polycystins: insights into polycystic kidney disease

Nature Reviews Nephrology volume 15, pages 412–422 (2019)Cite this article

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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.

Key points

  • The channel activity of polycystin 2 (PC2) at the primary cilium of renal collecting duct cells is independent of PC1.

  • Opening of PC2 is controlled by an internal hydrophobic gate; it is enhanced by membrane depolarization and an increase in intraciliary calcium.

  • PC1 and PC2 assemble in a 1:3 ratio in the PC1–PC2 complex.

  • PC1 might prevent cation permeation through the heteromeric PC1–PC2 complex by occluding the pore with three positively charged residues.

  • Extracellular polycystin domains in PC1 and PC2 are hot spots for pathogenic mutations.

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Fig. 1: The PC1–PC2 heteromeric complex.
Fig. 2: Closed and open states of PC2.
Fig. 3: Proposed mechanistic models for the gating of PC2.
Fig. 4: Ion channel function of PC2 at the primary cilium and the ER.

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Acknowledgements

The authors thank the Human Frontier Science Program, the Fondation pour la Recherche Médicale and the Agence Nationale de la Recherche for support.

Reviewer information

Nature Reviews Nephrology thanks S. Nauli and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Université Côte d’Azur, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut de Pharmacologie Moléculaire et Cellulaire, Labex ICST, Valbonne, France

    Dominique Douguet, Amanda Patel & Eric Honoré

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  1. Dominique Douguet
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E.H. wrote the manuscript, D.D. performed the structural modelling and A.P. edited the manuscript.

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Correspondence to Eric Honoré.

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Related links

ADPKD mutation database: http://pkdb.mayo.edu

HOLE program: http://www.holeprogram.org

Glossary

Primary cilium

Single non-motile cilium that lacks a central pair of microtubules present in all mammalian cells, except immune cells.

Permeation

Permeability of ions through channels.

Gating mechanism

Molecular mechanism of channel opening and closing.

Coiled-coil domains

Structural motifs in proteins in which 2–7 α-helices are coiled together and mediate protein–protein interaction.

Lipid nanodiscs

Lipid bilayer mimetics that function as synthetic model membranes in which purified proteins can be reconstituted for structural determination with cryo-electron microscopy.

Selectivity filter

Segment within the pore of an ion channel that controls its ionic permeability.

Voltage sensor

Charged domain of an ion channel (segment 4 (S4)) that confers voltage sensitivity.

Cation sink

Negative charges present at the extracellular side of the channel that attract cations towards the selectivity filter.

Conduction pathway

The pore of the ion channel.

EF-hand motif

Motif with a helix–loop–helix topology to which calcium ions bind.

Vestibule

The entrance of the ion channel pore.

Amphipathic

Contains both hydrophobic and hydrophilic groups.

Hydrophobic gate

Hydrophobic residue that repels water and prevents ion permeation through an ion channel.

π helix

Helix with 4.4 amino acids per turn; α-helices have 3.6 amino acids per turn.

Non-selective cationic channel

A channel permeable to all cations, including sodium, potassium and calcium.

Ratiometric calcium indicator

A calcium-imaging method based on the use of a ratio between two fluorescent intensities (for example, the Fura-2 calcium probe).

Mechanoprotection

Inhibition of mechanosensitive ion channels by the cytoskeleton.

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Douguet, D., Patel, A. & Honoré, E. Structure and function of polycystins: insights into polycystic kidney disease. Nat Rev Nephrol 15, 412–422 (2019). https://doi.org/10.1038/s41581-019-0143-6

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