Cryo-EM resolved the structure of the human cardiac myosin filament to 6 Å resolution, revealing the architecture of titin, cMyBP-C, and myosin motor domains for the first time.
Provides the first high-resolution cryo-EM structure of the human cardiac myosin filament, offering a structural basis for understanding cardiac contractility and the molecular mechanisms of cardiomyopathies.
Abstract Pumping of the heart is powered by filaments of the motor protein myosin, which pull on actin filaments to generate cardiac contraction. In addition to myosin, the filaments contain cardiac myosin-binding protein C (cMyBP-C), which modulates contractility in response to physiological stimuli, and titin, which functions as a scaffold for filament assembly 1 . Myosin, cMyBP-C and titin are all subject to mutation, which can lead to heart failure. Despite the central importance of cardiac myosin filaments to life, their molecular structure has remained a mystery for 60 years 2 . Here, we have solved the structure of the main (cMyBP-C-containing) region of the human cardiac filament to 6 Å resolution by cryo-EM. The reconstruction reveals the architecture of titin and cMyBP-C for the first time, and shows how myosin’s motor domains (heads) form 3 different types of motif (providing functional flexibility), which interact with each other and with specific domains of titin and cMyBP-C to dictate filament architecture and regulate function. A novel packing of myosin tails in the filament backbone is also resolved. The structure suggests how cMyBP-C helps generate the cardiac super-relaxed state 3 , how titin and cMyBP-C may contribute to length-dependent activation 4 , and how mutations in myosin and cMyBP-C might disrupt interactions, causing disease 5, 6 . A similar structure is likely in vertebrate skeletal myosin filaments. The reconstruction resolves past uncertainties, and integrates previous data on cardiac muscle structure and function. It provides a new paradigm for interpreting structural, physiological and clinical observations, and for the design of potential therapeutic drugs.
Dutta et al. (2023) studied Cardiac muscle structure. Cryo-electron microscopy (Cryo-EM) was evaluated on Molecular structure of the main region of the human cardiac filament. Cryo-EM resolved the structure of the human cardiac myosin filament to 6 Å resolution, revealing the architecture of titin, cMyBP-C, and myosin motor domains for the first time.