Fig. 2

TASK3 structure and variant locations. A We modeled TASK3 in an explicit environment and show the dimer colored by monomer. We omit the environment from other images for simplicity. B We mark the locations of variants observed in our cohort. Pink spheres mark sites of variants in one monomer and cyan sphere in the other. R303C and A320T fall outside of the modelable region. C We show the same view of TASK3, colored by features of the structure that we will use in describing the effects of genomic variants. We colored only one monomer since features overlap. The trans-membrane (TM) helices form the core of the structure and three of them form a type of 3-helix bundle (3-HB). TIG motifs form the lower section of the selectivity filter and are colored black. The C-terminus is predicted to fold along the intracellular-facing side and may participate in a gating mechanism. Most variants are on the intracellular-facing side or facing into the interior central chamber, indicated by an i. D G236R places positively charged Arginine side chains facing inside of the channel, not only occluding it but likely adding a cation blockade. E From our MD simulations, we also observed consistent conformational changes associated with G236R. F The variant M159I, which occurs within the 3-HBs, was also associated with a consistent change in N-terminal helix orientation. G Three different variants of R131 are observed and have effects on 3-HB organization and orientation relative to the N-terminal helix