@article{78212c7f5891424fad87d258798f95b9,
title = "The molecular basis for sarcomere organization in vertebrate skeletal muscle",
abstract = "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 {\AA} 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.",
keywords = "actin, electron tomography, muscle, myosin, sarcomere, structure, tropomyosin, Z-disc",
author = "Zhexin Wang and Michael Grange and Thorsten Wagner and Kho, {Ay Lin} and Mathias Gautel and Stefan Raunser",
note = "Funding Information: We thank M. Saur for preliminary work and J. Mahamid and J. Plitzko for advice on cryo-FIB milling. We are thankful to S. Tacke for hardware optimization for cryo-FIB and R.S. Goody for critical reading of the manuscript. We are grateful to O. Hofnagel and D. Prumbaum for EM support and B. Brandmeier for technical assistance. This work was supported by funds from the Max Planck Society (to S.R.), the Wellcome Trust (Collaborative Award in Sciences 201543/Z/16/Z to S.R. and M. Gautel), the European Research Council under the European Union{\textquoteright}s Horizon 2020 Programme ( ERC-2019-SyG 856118 to S.R. and M. Gautel), and the Medical Research Council ( MR/R003106/1 to M. Gautel and A.L.K.). M. Grange was supported by an European Molecular Biology Organization Long-Term Fellowship . M. Gautel holds the BHF Chair of Molecular Cardiology. Funding Information: We thank M. Saur for preliminary work and J. Mahamid and J. Plitzko for advice on cryo-FIB milling. We are thankful to S. Tacke for hardware optimization for cryo-FIB and R.S. Goody for critical reading of the manuscript. We are grateful to O. Hofnagel and D. Prumbaum for EM support and B. Brandmeier for technical assistance. This work was supported by funds from the Max Planck Society (to S.R.), the Wellcome Trust (Collaborative Award in Sciences 201543/Z/16/Z to S.R. and M. Gautel), the European Research Council under the European Union's Horizon 2020 Programme (ERC-2019-SyG 856118 to S.R. and M. Gautel), and the Medical Research Council (MR/R003106/1 to M. Gautel and A.L.K.). M. Grange was supported by an European Molecular Biology Organization Long-Term Fellowship. M. Gautel holds the BHF Chair of Molecular Cardiology. S.R. designed and supervised the project. A.L.K. and M. Gautel isolated mouse psoas myofibrils. Z.W. prepared cryo-lamellae, collected cryo-ET data, and performed sub-volume averaging. M. Grange optimized cryo-ET data acquisition. Z.W. and M. Grange annotated and analyzed the A-band and I-band data. Z.W. M. Grange, and T.W. analyzed Z-disc data. T.W. implemented tools for data analysis and automatic filament picking. Z.W. and M. Grange prepared figures and videos. Z.W. M. Grange, M. Gautel, and S.R. wrote the manuscript. All authors reviewed the results and commented on the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 The Author(s) Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2021",
month = apr,
day = "15",
doi = "10.1016/j.cell.2021.02.047",
language = "English",
volume = "184",
pages = "2135--2150.e13",
journal = "Cell",
issn = "0092-8674",
publisher = "Elsevier B.V.",
number = "8",
}