Extended Data Fig. 3. Modeling effects of SPTBN1 variants.

a–c, Potential coevolution of the closed conformation of the tandem calponin homology domain (CH1–CH2) of βII-spectrin (SPTBN1) (CH1 domain (teal), CH2 domain (red)), actinin-4 (ACTN4) (brown), and utrophin (UTRN) (purple)⁴⁷. d,e, Top hits from docking simulations of βII-spectrin’s CH1 (d) and CH2⁴⁸ (e) onto F-actin (gray). Domains in dark blue correspond to cryo-EM structure of the CH1 domain of βIII-spectrin bound to F-actin⁴⁹. f, Correct length of simulated interdomain linker (dark blue) in agreement with the orientation of the docked CH2 domain (red). g,h, Spatial distributions of the missense variants in βII-spectrin implicate disease mechanisms. g, Linear conformation of the entire 3D protein model is shown with the calponinhomology (CH) domains (CH1 and CH2) in the N-terminus (red), the spectrin repeats (SR) (green) and the pleckstrin homology (PH) domain in the C-terminus (purple). h, The 17 SR domains are superimposed with a minimal cartoon representation to emphasize the consistency of the 3D architecture despite high sequence diversity. The positions of the amino acid residues representing the missense variants are marked by gold-colored spheres.