Ion channel function of polycystin-2/polycystin-1 heteromer revealed by structure-guided mutagenesis

Staudner T, Khamseekaew J, Madej MG, Geiges L, Azemi B, Ziegler C, Korbmacher C, Ilyaskin A (2025)

Publication Type: Journal article

Publication year: 2025

Journal

DOI: 10.1002/1873-3468.70059

Abstract

Mutations in polycystin-1 (PC1) or polycystin-2 (PC2) cause autosomal-dominant polycystic kidney disease (ADPKD). Structural data suggest that one PC1 and three PC2 form heterotetrameric ion channels with an ion permeation pathway blocked by PC1 (R4100, R4107, and H4111) and PC2 (L677, N681) residues. Here, we demonstrate that replacing these residues with alanines results in a gain-of-function (GOF) PC2/PC1 construct with distinct selectivity properties compared to PC2 homomers. We also show preferential formation of PC2/PC1 heteromeric complexes over PC2 homomers. Re-interpretation of published PC2/PC1 cryo-electron microscopy data, combined with cysteine modification experiments, suggests that the pore-forming domain of PC1 adopts a canonical TRP channel-like conformation. This novel PC2/PC1 GOF construct offers the opportunity to investigate the functional impact of ADPKD mutations.

Authors with CRIS profile

Involved external institutions

Universität Regensburg Germany (DE)

How to cite

APA:

Staudner, T., Khamseekaew, J., Madej, M.G., Geiges, L., Azemi, B., Ziegler, C.,... Ilyaskin, A. (2025). Ion channel function of polycystin-2/polycystin-1 heteromer revealed by structure-guided mutagenesis. Febs Letters. https://doi.org/10.1002/1873-3468.70059

MLA:

Staudner, Tobias, et al. "Ion channel function of polycystin-2/polycystin-1 heteromer revealed by structure-guided mutagenesis." Febs Letters (2025).

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