Abstract
SummarySarcomeres 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.
Highlights
Skeletal muscle is an essential tissue required for efficient movement in vertebrates
Cryo-FIB milling combined with cryo-ET enabled us to visualize native vertebrate sarcomeres in three-dimensions with minimal artifacts or damage
Our structure of the actomyosin complex shows the complete myosin double head in the rigor state in molecular detail and pinpoints the essential chains (ELC)/regulatory light chains (RLC) interface as the position within myosin crucial for the structural rearrangement of the double head when bound to the thin filament
Summary
Skeletal muscle is an essential tissue required for efficient movement in vertebrates. Individual muscle fibers can be very large syncytia of up to several centimeters in length and are comprised of the force-generating and load-bearing devices of muscles called sarcomeres. The Z-disc is formed by the ends of antiparallel thin filaments from adjacent sarcomeres. These filaments are laterally cross-linked by a-actinin (Ribeiro et al, 2014; Takahashi and Hattori, 1989), forming an intricate network with other proteins such as titin, nebulin, and myotilin (Gontier et al, 2005; Gregorio et al, 1998; Lange et al, 2006). The network formed by these proteins and myosin filaments provide mechanical stability for the sarcomere by absorbing misbalanced longitudinal force produced by myosin heads. Deformation of the M-band by shear forces could allow it to act as a strain sensor and play an important role in signaling (Gautel, 2011; Gautel and Djinovic-Carugo, 2016; Lange et al, 2020)
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