The research teams led by Sun Fei from the Institute of Biophysics, Chinese Academy of Sciences, and Li Guohui from the Dalian Institute of Chemical Physics, jointly uncovered the in situ structural basis of excitation-contraction coupling mediated by the triad in mammalian skeletal muscle. The relevant paper was published on March 20th in Advanced Science.
In living organisms, the contraction and relaxation of skeletal muscles are controlled by the nervous system. Chemical signals transmitted by the nervous system undergo a series of transformations and transmissions, ultimately resulting in the mechanical contraction of muscles, a process known as excitation-contraction coupling. In this process, RyR1 on the triad plays a crucial role in transmitting excitation signals throughout the excitation-contraction coupling process. However, despite the high-resolution structure of RyR1 being resolved, there remain several important scientific questions regarding RyR1 function that have not been answered.
In this study, building upon previous work, the research team led by Sun Fei employed tissue in situ sample preparation methods and cryo-electron tomography three-dimensional reconstruction technology to systematically characterize the fine in situ structure of the triad in skeletal muscle. This includes: resolving the in situ structure of RyR1 in skeletal muscle at 16.7 Å resolution, discovering the tight binding of RyR1 with FKBP12 and Calmodulin (CaM) in the in situ environment; resolving the in situ structure of the RyR1-DHPR supercomplex, identifying two connecting densities, confirming the physical interaction between RyR1 and DHPR; discovering the "right-handed" diagonal arrangement pattern of RyR1 in skeletal muscle in situ, with the four DHPRs forming a tetramer binding to RyR1 at a 1:2 ratio; molecular dynamics simulations demonstrating the necessity of the "right-handed" diagonal arrangement of RyR1 for its coordinated calcium release, explaining relevant genetic pathological data. These research findings provide key evidence for the physical coupling between RyR1 and DHPR, offering important clues for a deeper understanding of the molecular mechanism of excitation-contraction coupling in skeletal muscle.
Related Paper Information: https://doi.org/10.1126/sciadv.adl1126
