The molecular basis for sarcomere organization in vertebrate skeletal muscle

Abstract

<p id="d2534398e178">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. </p><div class="fig panel" id="undfig1"> <a class="named-anchor" id="undfig1"> <!-- named anchor --> </a> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/d422a0ec-d021-4159-b4b7-1022c5eba5b0/PubMedCentral/image/fx1"/> </div> <div class="panel-content"/> </div><p id="d2534398e188"> <div class="list"> <a class="named-anchor" id="ulist0010"> <!-- named anchor --> </a> <ul class="so-custom-list" style="list-style-type: none"> <li id="u0010"> <div class="so-custom-list-label so-ol">•</div> <div class="so-custom-list-content so-ol"> <p id="p0010">Three-dimensional sarcomere organization and plasticity at the molecular level</p> </div> </li> <li id="u0015"> <div class="so-custom-list-label so-ol">•</div> <div class="so-custom-list-content so-ol"> <p id="p0015">Myosin double heads can adopt two different interactions with actin filaments</p> </div> </li> <li id="u0020"> <div class="so-custom-list-label so-ol">•</div> <div class="so-custom-list-content so-ol"> <p id="p0020">Transition between tropomyosin states happens within one tropomyosin unit</p> </div> </li> <li id="u0025"> <div class="so-custom-list-label so-ol">•</div> <div class="so-custom-list-content so-ol"> <p id="p0025">An irregular mesh of α-actinin doublets cross-links antiparallel actin filaments</p> </div> </li> </ul> </div> </p><p class="first" id="d2534398e211">Visualizing the mouse sarcomere in the rigor state using electron cryo-tomography reveals architectural details of the different zones and provides insight into how key factors are arranged within them to support function during muscle contraction. </p>