Abstract
Contraction of striated muscles is driven by cyclic interactions of myosin head projecting from the thick filament with actin filament and is regulated by Ca2+ released from sarcoplasmic reticulum. Muscle thin filament consists of actin, tropomyosin and troponin, and Ca2+ binding to troponin triggers conformational changes of troponin and tropomyosin to allow actin-myosin interactions. However, the structural changes involved in this regulatory mechanism remain unknown. Here we report the structures of human cardiac muscle thin filament in the absence and presence of Ca2+ by electron cryomicroscopy. Molecular models in the two states built based on available crystal structures reveal the structures of a C-terminal region of troponin I and an N-terminal region of troponin T in complex with the head-to-tail junction of tropomyosin together with the troponin core on actin filament. Structural changes of the thin filament upon Ca2+ binding now reveal the mechanism of Ca2+ regulation of muscle contraction.
Highlights
Contraction of striated muscles is driven by cyclic interactions of myosin head projecting from the thick filament with actin filament and is regulated by Ca2+ released from sarcoplasmic reticulum
The sample for cryoEM image analysis was prepared by reconstitution with actin filament from skeletal muscle, recombinant cardiac Tm and Tn as a ternary complex of troponin C (TnC), troponin I (TnI), and troponin T (TnT) (Supplementary Fig. 1)
To visualize the density of Tn in the three-dimensional (3D) image reconstruction, helical image reconstruction conventionally used for the structural analysis of actin filament cannot be used because it smears out the Tn density[5,7]
Summary
Contraction of striated muscles is driven by cyclic interactions of myosin head projecting from the thick filament with actin filament and is regulated by Ca2+ released from sarcoplasmic reticulum. 1234567890():,; Muscle contraction occurs through mutual sliding between the thick and thin filaments[1,2] by repeated association and dissociation of myosin head and actin filament coupled with ATP binding, hydrolysis and release by myosin head[3]. The binding of Ca2+ to TnC triggers this structural switching to the Ca2+-on state This regulatory mechanism is specific to striated muscles. Tn binds to a specific position of Tm, making its periodicity 385 Å corresponding to the actin strand of seven subunits, making the stoichiometry of actin, Tm, and Tn 7:1:16
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