Figure 6. Schematic drawing of the thin-filament functional unit.

Seven actin monomers (gray) spanned by 1 tropomyosin dimmer (red) and 1 troponin complex: cardiac troponin C (cTnC; pink), cardiac troponin I (cTnI; blue), and cardiac troponin T (cTnT; orange). Capitals N and C depict N- and C-terminal protein ends, respectively. Dark-blue tropomyosin depicts near-neighbor tropomyosin dimmer interaction.^69,70 The orientation of thin-filament proteins is as follows: the N-terminal region of cTnT points toward the pointed end (M-band), whereas the core domain of the troponin complex is oriented to the barbed end (Z-disk).⁷¹ Interacting sites and structural location of actin–tropomyosin–troponin proteins are matched in accordance with available literature.^{25,50,51,55,70,72} Cardiac TnI residues 1 to 34 are arbitrarily positioned. Our drawing follows the proposed mechanism for Ca²⁺-regulation of contraction proposed by Murakami et al.⁵⁵ A, B-state (blocked); when ATP is present and cytoplasmic [Ca²⁺] is low such that Ca²⁺ is not bound to cTnC, tropomyosin sterically blocks the myosin-binding sites on F-actin. B, C-state (Ca²⁺-induced); cytoplasmic [Ca²⁺] rises such that Ca²⁺ binds to cTnC inducing conformational changes of the troponin complex, resulting in an ≈25° movement of tropomyosin on the thin filament, thereby exposing most of the myosin-binding sites on F-actin. Note the movement of tropomyosin away from subdomains 1 and 2 of F-actin. In the C-state, the myofilament is not yet activated because nontension-generating cross-bridges bind weakly to F-actin. C, M-state (myosin-induced); involves the strong binding of tension-generating cross-bridges that induce an additional ≈10° movement of tropomyosin on F-actin, resulting in myofilament activation and contraction. Note the transition of tropomyosin into subdomains 3 and 4 of F-actin. D, Solid arrows depict the location of mutation sites on thin-filament proteins present in our human HCM samples. Cardiac TnT residues 1 to 65 are shortened to fit the enlarged scale.