Cryo-EM structure of the human cardiac myosin filament
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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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- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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