Energetic landscape of polycystin channel gating

Members of the polycystin family (PKD2 and PKD2L1) of transient receptor potential (TRP) channels conduct Ca 2+ and depolarizing monovalent cations. Variants in PKD2 cause autosomal dominant polycystic kidney disease (ADPKD) in humans, whereas loss of PKD2L1 expression causes seizure susceptibility in mice. Understanding structural and functional regulation of these channels will provide the basis for interpreting their molecular dysregulation in disease states. However, the complete structures of polycystins are unresolved, as are the conformational changes regulating their conductive states. To provide a holistic understanding of the polycystin gating cycle, we use computational prediction tools to model missing PKD2L1 structural motifs and evaluate more than 150 mutations in an unbiased mutagenic functional screen of the entire pore module. Our results provide an energetic landscape of the polycystin pore, which enumerates gating sensitive sites and interactions required for opening, inactivation, and subsequent desensitization. These findings identify the external pore helices and specific cross‐domain interactions as critical structural regulators controlling the polycystin ion channel conductive and nonconductive states. Synopsis Conformational changes that open polycystins are critical for their ion channel function in brain and kidney. Results from an unbiased functional screen of the entire polycystin pore module and AI‐driven structural modeling provide an energetic landscape while enumerate gating‐sensitive sites controlling the conductive states of the channel. External pore helix interactions regulate the polycystin channel opening. Opening the inner and outer pore gates are energetically coupled. Inactivation and desensitized are structurally related states controlled by specific inter‐subunit interactions between the pore helix 1 and sixth transmembrane segment. Graphical Abstract Conformational changes that open polycystins are critical for their ion channel function in brain and kidney. Results from an unbiased functional screen of the entire polycystin pore module and AI‐driven structural modeling provide an energetic landscape while enumerate gating‐sensitive sites controlling the conductive states of the channel.