Figure 1.

Architecture of Na_V, CaM, and FGFs.A, schematic of human Na_V. The α-subunit N-terminal domain (NTD, cyan), transmembrane domains DI-DIII (pale green) and DIV (gray), the linker connecting DIII to DIV (orange), and C-terminal domain (CTD, green) with 4-helix bundle EFL (dark green) that binds FGFs (light gray), and IQ motif that binds CaM (CaM_N/blue, CaM_C/red) are shown. Auxiliary β-subunit that contains a transmembrane helix and extracellular domain is lavender. B, model of apo CaM and FGF12B bound to Na_V. Model is comprised of Na_VPAS (5X0M, DI-DIII/pale green surface, DIV voltage-sensing domain/gray surface, DIV pore domain/black surface, DIII-DIV linker/orange cartoon), the Na_V1.5_CTD (4DCK, forest green), the apo CaM+Na_V1.2_IQp ensemble (6BUT, CaM_N/blue, CaM_C/red), and FGF12B (1Q1U, gray). The Na_V1.5_CTD was aligned to Na_VPAS EFL (a.a. 1426–1521), the apo CaM+Na_V1.2_IQp ensemble was aligned with 4DCK via CaM a.a. 101–112 and 117–128, and FGF12B was aligned with 4DCK using FGF13B a.a. 11–158. For simplicity Na_V1.2_IQp in 6BUT and CaM FGF13B in 4DCK are not shown. C, schematics of FGF11 (orange), FGF12A (purple), FGF13A (red), and FGF14 (blue) splice variants. The β-trefoil core is shown as a rectangle, and the long-term inactivation particle (LTP, green) and putative CaM-binding domain (CaMBD, limon) are shown as cylinders. D, predicted likelihood of disorder of A-type FGF isoform sequences. The minima shaded green and limon correspond to the LTP and CaMBD sequences, respectively. The folded β-trefoil core is shaded gray. E and F, sequence alignments of the A-type FGF LTP (E) and CaMBD (F). Positions that are conserved in at least three of the four FGF isoforms are shaded (LTP/green, CaMBD/limon). Positions in the CaMBD (F) that contain a basic K or R in all four isoforms are shaded in pale yellow. Alignments were made with COBALT (108).