Thin filament dysfunctions caused by mutations in tropomyosin Tpm3.12 and Tpm1.1

Fig. 1. Distribution of differences in amino acid sequences of Tpm1.1 and Tpm3.12 (a). Substitutions in Tpm1.1 and Tpm3.12 linked to cardiomyopathy and myopathy-causing mutations in TPM1 and TPM3 (b). Regions of tropomyosin interactions with proteins of the thin filament (c). The alignment of Tpm1.1 and Tpm3.12 sequences with respect to seven actin-binding periods (P1–P7) was adapted from Barua et al. (2011). Conservative and non-conservative substitutions, which distinguish Tpm1.1 from Tpm3.12 are marked in green and yellow, respectively. Amino acid residues corresponding to heptapeptide repeat of the coiled coil (a–g) are shown on top of the sequences; the consensus sites which potentially interact with residues exposed on actin surface are marked with *. HCM: hypertrophic cardiomyopathy; DCM: dilated cardiomyopathy; NM: nemaline myopathy; CFTD: congenital fiber type disproportion. (Color figure online)

Fig. 2. Tropomyosin interactions within the coiled coil (a), in the overlap between adjacent tropomyosin molecules (b) and with F-actin in the B- C- and M-state (c). Coiled-coil stabilization by hydrophobic interactions between a and d residues at the interface between α-helices and by corresponding electrostatic interactions between e and g residues within two turns of α-helices (heptapeptide). NMR structure of the C-terminus (light grey) and N-terminus (dark grey) of tropomyosin Tpm1.1 model peptides showing the overlap region of tropomyosin (PDB: 2G9 J); consensus, actin-binding sites (Lys6, Met10, Lys12, Asp254, Asp255, Asp258) are shown in red sticks. For illustration of the azimuthal positions of tropomyosin in the B-, C- and M-state, tropomyosin segment comprising residues 148–284 (PDB: 6bno) was aligned in PyMol on F-actin (PDB: 1c1 g). Pro333 (green spheres) was used as a marker of the boundary between the C- and B-state positions (Kiani et al. 2019). (Color figure online)

Fig. 3. Schematic illustration of pointed end capping by Tmod (a) or Lmod (b) and formation of actin polymerization nuclei by Lmod (c). Actin subunits and tropomyosin chains are marked with grey and green, respectively. TpmBS1 and TpmBS2—tropomyosin-binding sites 1 and 2; ABS1 and ABS2—actin-binding sites 1 and 2, WH2—WASP homology 2 domain. The drawing is based on the models proposed in (Chen et al. 2015; Rao et al. 2014). (Color figure online)