Fig. 2: Structural comparison between TRPC1/C5 heteromer and TRPC5 homomer.

a Structural superposition of the global transmembrane domain of TRPC1/C5 heteromer and TRPC5 homomer, as viewed from the extracellular region. Voltage-sensing-like domain is highlighted at each edge to emphasize the movements with red arrows. Translations of the outer helices are indicated in angstroms (Å). b Single protomer overlap of TRPC1 with TRPC5 within TRPC1/C5 heteromer and TRPC5 homomer. ARD, ankyrin repeat domain; HLH, helix–loop–helix; PH, pore helix; CH, connecting helix; CCD, coiled-coil domain. TRPC1 displays an outward tilting of the S2–S3 linker, which also results in a tilted position of the S2 helix. On the right, movements of the S2 and S3 helices are highlighted within the dotted box, showing both tilting and translational shifts. c Intracellular view of TRPC1/C5 heteromer (bottom) depicted with quadrilaterals connecting residues on the S6 helix. For comparison, the TRPC5 homomer (top) is drawn alongside. d Top view of the TRPC1/C5 heteromer and TRPC5 homomer (left) and a zoomed-in view of the selectivity filter (right). Densities near the selectivity pore, along with pore-forming or neighboring residues in each subunit, are shown. e Sequence alignment of the selectivity filter-forming region of TRPC1 and TRPC5 in different species (human, Homo sapiens; mouse, Mus musculus; rat, Rattus norvegicus; bovine, Bos taurus). f Ion conduction pathways of each TRPC5 homomer and TRPC1/C5 heteromer, calculated using MOLE⁵⁴, are shown as black density, highlighting the asymmetric pathway in the heteromer. Residues at the selectivity filter are highlighted by their backbone traces, and those lining the pore constriction site are also shown. g Densities of the pore constriction site and their corresponding residues. H646 in the TRPC1 subunit tightly constricts the pore in addition to N625 in the TRPC5 subunits. h Sequence alignment of the S6 helix demonstrating the differences in residues conserved across species between TRPC1 and TRPC5. i Electrostatic potential surface (scale in kcal mol⁻¹e⁻¹) of the heteromer and the homomer was calculated using ChimeraX⁵⁶. j Densities of the pore cavity with its corresponding residues are shown: K639 (TRPC1) and N618 (TRPC5). k Pore radius calculation using HOLE⁵⁵.