The molecular basis for sarcomere organization in vertebrate skeletal muscle

Wang Z, Grange M, Wagner T, Khoo AL, Gautel M, Raunser S (2021) Cell 

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Sarcomeres are force-generating and load-bearing devices of muscles. A precise molecular picture of how sarcomeres are built underpins understanding their role in health and disease. Here, we determine the molecular architecture of native vertebrate skeletal sarcomeres by electron cryo-tomography. Our reconstruction reveals molecular details of the three-dimensional organization and interaction of actin and myosin in the A-band, I-band, and Z-disc and demonstrates that α-actinin cross-links antiparallel actin filaments by forming doublets with 6-nm spacing. Structures of myosin, tropomyosin, and actin at ~10 Å further reveal two conformations of the “double-head” myosin, where the flexible orientation of the lever arm and light chains enable myosin not only to interact with the same actin filament, but also to split between two actin filaments. Our results provide unexpected insights into the fundamental organization of vertebrate skeletal muscle and serve as a strong foundation for future investigations of muscle diseases.

Sarcomere organization at molecular level. Row 1 shows a schematic representation of the sarcomere. Row 2 shows the three-dimensional sarcomere organization and plasticity at the molecular level (filaments: pink and green, a-Actinin: blue). Row 3: Interaction of muscle proteins in detail. First two bubbles show the interaction of the myosin heads (yellow, orange, red) with actin (green). Third bubble shows details of actin, tropomyosin and troponin in the A-band. Last bubble depicts irregular mesh of a-Actinin (blue) cross-linking actin filaments (green, pink) in the Z-disc.

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