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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\u2010of\u2010function (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\u2010interpretation of published PC2\/PC1 cryo\u2010electron microscopy data, combined with cysteine modification experiments, suggests that the pore\u2010forming domain of PC1 adopts a canonical TRP channel\u2010like conformation. This novel PC2\/PC1 GOF construct offers the opportunity to investigate the functional impact of ADPKD mutations.<\/jats:p>","DOI":"10.1002\/1873-3468.70059","type":"journal-article","created":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T06:43:46Z","timestamp":1747032226000},"page":"1649-1668","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Ion channel function of polycystin\u20102\/polycystin\u20101 heteromer revealed by structure\u2010guided mutagenesis"],"prefix":"10.1002","volume":"599","author":[{"given":"Tobias","family":"Staudner","sequence":"first","affiliation":[{"name":"Institute of Cellular and Molecular Physiology, Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juthamas","family":"Khamseekaew","sequence":"additional","affiliation":[{"name":"Institute of Cellular and Molecular Physiology, Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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