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    Cryo-EM structure of the human cardiac myosin filament [preprint]

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    Authors
    Dutta, Debabrata
    Nguyen, Vu
    Campbell, Kenneth S
    Padrón, Raúl
    Craig, Roger
    UMass Chan Affiliations
    Radiology
    Padrón-Craig Lab
    Document Type
    Preprint
    Publication Date
    2023-04-12
    Keywords
    Biophysics
    myosin
    
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    Link to Full Text
    https://doi.org/10.1101/2023.04.11.536274
    Abstract
    Pumping of the heart is powered by filaments of the motor protein myosin, which pull on actin filaments to generate cardiac contraction. In addition to myosin, the filaments contain cardiac myosin-binding protein C (cMyBP-C), which modulates contractility in response to physiological stimuli, and titin, which functions as a scaffold for filament assembly 1 . Myosin, cMyBP-C and titin are all subject to mutation, which can lead to heart failure. Despite the central importance of cardiac myosin filaments to life, their molecular structure has remained a mystery for 60 years 2 . Here, we have solved the structure of the main (cMyBP-C-containing) region of the human cardiac filament to 6 Å resolution by cryo-EM. The reconstruction reveals the architecture of titin and cMyBP-C for the first time, and shows how myosin's motor domains (heads) form 3 different types of motif (providing functional flexibility), which interact with each other and with specific domains of titin and cMyBP-C to dictate filament architecture and regulate function. A novel packing of myosin tails in the filament backbone is also resolved. The structure suggests how cMyBP-C helps generate the cardiac super-relaxed state 3 , how titin and cMyBP-C may contribute to length-dependent activation 4 , and how mutations in myosin and cMyBP-C might disrupt interactions, causing disease 5, 6 . A similar structure is likely in vertebrate skeletal myosin filaments. The reconstruction resolves past uncertainties, and integrates previous data on cardiac muscle structure and function. It provides a new paradigm for interpreting structural, physiological and clinical observations, and for the design of potential therapeutic drugs.
    Source
    Dutta D, Nguyen V, Campbell KS, Padrón R, Craig R. Cryo-EM structure of the human cardiac myosin filament. bioRxiv [Preprint]. 2023 Apr 12:2023.04.11.536274. doi: 10.1101/2023.04.11.536274. PMID: 37090534; PMCID: PMC10120621.
    DOI
    10.1101/2023.04.11.536274
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/52021
    PubMed ID
    37090534
    Notes
    This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.
    Rights
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
    ae974a485f413a2113503eed53cd6c53
    10.1101/2023.04.11.536274
    Scopus Count
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    Radiology Publications
    Padrón-Craig Lab

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