Figure 2. Apparently tolerated missense... | Rockefeller University Press

Figure 2.

Apparently tolerated missense mutation locations in the thin filament.(A) The low-Ca2+ condition cardiac thin filament is shown, with the TnC subunit hidden to better view the other two subunits of the troponin core domain. Filament orientation is the same as in Fig. 1. Bright green spheres indicate TnI and TnI residues that are apparently tolerant of mutation. These residues have at least one amino acid substitution detected in gnomAD sequencing of >130,000 individuals, and no substitutions were judged pathogenic or VUS in the current dataset. They are widely distributed and not confined to the actin-tropomyosin surface. (B) In greater close-up, selected features of the Ca2+-saturated state of the thin filament (from PDB accession no. 6kn8; Yamada et al., 2020), the structure that would be present in contracting muscle. TnC (translucent pale green) is shown, and both TnI and TnT are hidden. Note the relative paucity of bright green, apparently tolerated mutation sites in the N-lobe, relative to either the C-lobe of TnC or (in A) the remainder of troponin. Also note that the TnC N-lobe makes multiple close contacts: with actin (gray) and tropomyosin (black, seen behind the translucent TnC), as well as with TnI (not depicted) and with the Ca2+ ion that is the primary on-off switch for contraction.

Apparently tolerated missense mutation locations in the thin filament. (A) The low-Ca²⁺ condition cardiac thin filament is shown, with the TnC subunit hidden to better view the other two subunits of the troponin core domain. Filament orientation is the same as in Fig. 1. Bright green spheres indicate TnI and TnI residues that are apparently tolerant of mutation. These residues have at least one amino acid substitution detected in gnomAD sequencing of >130,000 individuals, and no substitutions were judged pathogenic or VUS in the current dataset. They are widely distributed and not confined to the actin-tropomyosin surface. (B) In greater close-up, selected features of the Ca²⁺-saturated state of the thin filament (from PDB accession no. 6kn8; Yamada et al., 2020), the structure that would be present in contracting muscle. TnC (translucent pale green) is shown, and both TnI and TnT are hidden. Note the relative paucity of bright green, apparently tolerated mutation sites in the N-lobe, relative to either the C-lobe of TnC or (in A) the remainder of troponin. Also note that the TnC N-lobe makes multiple close contacts: with actin (gray) and tropomyosin (black, seen behind the translucent TnC), as well as with TnI (not depicted) and with the Ca²⁺ ion that is the primary on-off switch for contraction.