Fig. 6.

Schematic diagram of a half-sarcomere illustrating thin-filament transitions, in the absence of Ca²⁺. The average length of the thin filament (half-sarcomere) is 1.05 μm (60, 61), which consists of a 38.5-nm periodicity of the actin–tropomyosin–troponin (A₇TmTn, functional unit) complex (62, 63), i.e., each half-thin filament consists of 27 A₇TmTn units (red and green rectangular boxes depict functional units). The length of the thick filament is ∼1.63 μm. After subtracting the thick-filament bare zone (M-band region that is deprived of myosin heads; 0.16 μm), the thick-filament length per half-sarcomere is ∼0.74 μm (64). Because the distance between myosin helical repeats is 42.9 nm (on the same axis layer) (65), ∼18 myosins occupy each half-thick filament. (A) Solution studies indicate that ∼95% of the myofilaments in the free Ca²⁺ state are blocked (B state) in the absence of cardiac myosin-binding protein C (cMyBP-C) (10). This indicates that ∼26 A₇TmTn units are blocked (depicted in red) and only a single unit of A₇TmTn is in the C-state position (depicted in green) per half-thin filament. The single “C”-state functional unit is randomly drawn in the scheme. This situation parallels cMyBP-C truncating mutations, where reduced total cMyBP-C protein levels have been found (22, 23). Please note that for clarity no cMyBP-C is shown (i.e., mimicking full lack of cMyBP-C). (B) In the presence of cMyBP-C, more myosin-binding sites are available on actin, because the N-terminal extension of cMyBP-C dislocates tropomyosin into the C-state position (20, 21) (depicted as seven green functional units). Assuming that cardiac muscle contains a minimum of seven cMyBP-C at regular intervals of 43 nm starting from “stripe” 5–11 in the C zone (215 nm from the M band) (66), cMyBP-C would coincide with the second to third myosin counting from the M band in the scheme. This situation mimics healthy donor samples. (C) Mutations in troponin subunits disrupt troponin–tropomyosin interactions, which causes the thin filament to be less blocked. As shown in the picture, more functional units are in the C state.