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- EMDB-40468: In situ human cardiac thick filament in the relaxed state -

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Basic information

Entry
Database: EMDB / ID: EMD-40468
TitleIn situ human cardiac thick filament in the relaxed state
Map dataHuman cardiac thick filament in the relaxed state
Sample
  • Complex: In situ human cardiac thick filament in the relaxed state
Keywordsmyosin / cMyBP-C / titin / STRUCTURAL PROTEIN
Biological speciesHomo sapiens (human)
Methodsubtomogram averaging / cryo EM / Resolution: 16.5 Å
AuthorsChen L / Liu J / Rastegarpouyani H / Janssen PML / Pinto JR / Taylor KA
Funding support United States, 6 items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL128683 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL160966 United States
National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS)R21 AR077802 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI087846 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI152421 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35 GM139616 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2024
Title: Structure of mavacamten-free human cardiac thick filaments within the sarcomere by cryoelectron tomography.
Authors: Liang Chen / Jun Liu / Hosna Rastegarpouyani / Paul M L Janssen / Jose R Pinto / Kenneth A Taylor /
Abstract: Heart muscle has the unique property that it can never rest; all cardiomyocytes contract with each heartbeat which requires a complex control mechanism to regulate cardiac output to physiological ...Heart muscle has the unique property that it can never rest; all cardiomyocytes contract with each heartbeat which requires a complex control mechanism to regulate cardiac output to physiological requirements. Changes in calcium concentration regulate the thin filament activation. A separate but linked mechanism regulates the thick filament activation, which frees sufficient myosin heads to bind the thin filament, thereby producing the required force. Thick filaments contain additional nonmyosin proteins, myosin-binding protein C and titin, the latter being the protein that transmits applied tension to the thick filament. How these three proteins interact to control thick filament activation is poorly understood. Here, we show using 3-D image reconstruction of frozen-hydrated human cardiac muscle myofibrils lacking exogenous drugs that the thick filament is structured to provide three levels of myosin activation corresponding to the three crowns of myosin heads in each 429Å repeat. In one crown, the myosin heads are almost completely activated and disordered. In another crown, many myosin heads are inactive, ordered into a structure called the interacting heads motif. At the third crown, the myosin heads are ordered into the interacting heads motif, but the stability of that motif is affected by myosin-binding protein C. We think that this hierarchy of control explains many of the effects of length-dependent activation as well as stretch activation in cardiac muscle control.
History
DepositionApr 13, 2023-
Header (metadata) releaseFeb 21, 2024-
Map releaseFeb 21, 2024-
UpdateMar 6, 2024-
Current statusMar 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40468.png

Downloads & links

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Map

FileDownload / File: emd_40468.map.gz / Format: CCP4 / Size: 27 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHuman cardiac thick filament in the relaxed state
Voxel sizeX=Y=Z: 4.2368 Å
Density
Contour LevelBy AUTHOR: 0.115
Minimum - Maximum-0.63768333 - 0.6925983
Average (Standard dev.)0.025764126 (±0.035650723)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-96-96-96
Dimensions192192192
Spacing192192192
CellA=B=C: 813.46564 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Curved layer composed of five human cardiac myosin II tail of IHM-C.

Fileemd_40468_additional_1.map
AnnotationCurved layer composed of five human cardiac myosin II tail of IHM-C.
Projections & Slices
AxesZYX

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Slices (1/2)
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Additional map: Curved layer composed of five human cardiac myosin II tail of IHM-D.

Fileemd_40468_additional_2.map
AnnotationCurved layer composed of five human cardiac myosin II tail of IHM-D.
Projections & Slices
AxesZYX

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Additional map: Curved layer composed of five human cardiac myosin II tail of IHM-S.

Fileemd_40468_additional_3.map
AnnotationCurved layer composed of five human cardiac myosin II tail of IHM-S.
Projections & Slices
AxesZYX

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Additional map: Human cardiac myosin II tail of IHM-D segmented...

Fileemd_40468_additional_4.map
AnnotationHuman cardiac myosin II tail of IHM-D segmented from three stacked repeating units of the thick filament backbone map
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Additional map: Human cardiac myosin II tail of IHM-S segmented...

Fileemd_40468_additional_5.map
AnnotationHuman cardiac myosin II tail of IHM-S segmented from three stacked repeating units of the thick filament backbone map
Projections & Slices
AxesZYX

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Histogram

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Additional map: Human cardiac myosin II tail of IHM-C segmented...

Fileemd_40468_additional_6.map
AnnotationHuman cardiac myosin II tail of IHM-C segmented from three stacked repeating units of the thick filament backbone map
Projections & Slices
AxesZYX

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Additional map: cMyBP-C domains C8, C9, C10

Fileemd_40468_additional_7.map
AnnotationcMyBP-C domains C8, C9, C10
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Additional map: Eleven domains of C-zone titin-C

Fileemd_40468_additional_8.map
AnnotationEleven domains of C-zone titin-C
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AxesZYX

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Additional map: Eleven domains of C-zone titin-M

Fileemd_40468_additional_9.map
AnnotationEleven domains of C-zone titin-M
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Half map: Human cardiac thick filament in the relaxed state even half map

Fileemd_40468_half_map_1.map
AnnotationHuman cardiac thick filament in the relaxed state even half map
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Half map: Human cardiac thick filament in the relaxed state odd half map

Fileemd_40468_half_map_2.map
AnnotationHuman cardiac thick filament in the relaxed state odd half map
Projections & Slices
AxesZYX

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Slices (1/2)
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Sample components

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Entire : In situ human cardiac thick filament in the relaxed state

EntireName: In situ human cardiac thick filament in the relaxed state
Components
  • Complex: In situ human cardiac thick filament in the relaxed state

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Supramolecule #1: In situ human cardiac thick filament in the relaxed state

SupramoleculeName: In situ human cardiac thick filament in the relaxed state
type: complex / ID: 1 / Parent: 0
Source (natural)Organism: Homo sapiens (human)

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Experimental details

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Structure determination

Methodcryo EM
Processingsubtomogram averaging
Aggregation statetissue

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Sample preparation

BufferpH: 6.8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 6.0 µm / Nominal defocus min: 6.0 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 1.5 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

ExtractionNumber tomograms: 5 / Number images used: 11369
Final angle assignmentType: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 16.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number subtomograms used: 757
FSC plot (resolution estimation)

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