The DOI matches its Crossref record; 78 of the 78 references it cites were found in a registry or an index.
Cryo-EM structure of the human cardiac myosin filament
Open accessPublished version of a preprint
Abstract
Pumping of the heart is powered by filaments of the motor protein myosin that 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 solve the structure of the main (cMyBP-C-containing) region of the human cardiac filament using cryo-electron microscopy. The reconstruction reveals the architecture of titin and cMyBP-C and shows how myosin's motor domains (heads) form three different types of motif (providing functional flexibility), which interact with each other and with titin and cMyBP-C to dictate filament architecture and function. The packing of myosin tails in the filament backbone is also resolved. The structure suggests how cMyBP-C helps to 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 disturb interactions, causing disease 5,6. 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.
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Metadata
- Authors
- Dutta, D., Nguyen, V., Campbell, K. S., Padrón, R., & Craig, R.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- University of Kentucky (US)
- Corresponding author
- Dutta, Debabrata
- Padrón, Raúl
- Craig, Roger
- Venue
- Nature
- Published
- 2023-11-01
- Volume
- 623
- Issue
- 7988
- Pages
- 853-862
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC10846670
- OpenAlex
- W4388142164
- Cited by
- 164
- References
- 78
- Citations by year
- 2026: 49 · 2025: 54 · 2024: 44 · 2023: 17
- FWCI
- 32.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (HL139883, HL164560, HL148785, HL149164)
- University of California, San Francisco
- National Heart, Lung, and Blood Institute (R01HL139883, R01HL149164, R01HL148785, R01HL164560)
- National Institute of General Medical Sciences (R01GM129325)
- National Institute of Allergy and Infectious Diseases
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR072036, R01AR081941)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Advanced Electron Microscopy Techniques and Applications
- Keywords
- myosin binding protein C, titin, myosin motor domain, super-relaxed state, length-dependent activation, heart failure, cardiac contractility, sarcomere structure, myosin mutations
- MeSH terms
- Myosin Binding Protein C, Carrier Proteins, Humans, Myocardium, Cryoelectron Microscopy, Cardiac Myosins, Connectin
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