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Significance How do variants that cause autosomal dominant polycystic kidney disease (ADPKD) alter the structure and function of polycystin-2 channels? This 20-y-old question remains unanswered because polycystins traffic to organelle membranes, such as the primary cilia, that are challenging locations to study. Here, we focus on the molecular impact of variants found in the TOP domain of polycystin-2, a site commonly mutated in ADPKD. We report the C331S variant structure, where the TOP domain is destabilized by the localized mutation. We find that TOP domain variant channels still assemble but fail to open at normal voltages. Importantly, these variant channels retain their native primary cilia trafficking, suggesting their availability to drug modulators as a rationale for ADPKD treatment.

Molecular dysregulation of ciliary polycystin-2 channels caused by variants in the TOP domain