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- EMDB-25918: Cardiac thin filament decorated with C1 Ig-domain and regulatory ... -

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Basic information

Entry
Database: EMDB / ID: EMD-25918
TitleCardiac thin filament decorated with C1 Ig-domain and regulatory M-domain of cardiac myosin binding protein C (cMyBP-C)
Map dataTHM of the regulatory M-domain and C1 Ig-domain of cMyBP-C bound to cardiac thin filament
Sample
  • Complex: Cardiac thin filament decorated with C1 Ig-domain and regulatory M-domain of cardiac myosin binding protein C (cMyBP-C)
    • Protein or peptide: cardiac actin
    • Protein or peptide: Myosin-binding protein C, cardiac-type
    • Protein or peptide: tropomyosin model
Function / homology
Function and homology information


C zone / regulation of muscle filament sliding / striated muscle myosin thick filament / cardiac myofibril / regulation of striated muscle contraction / Striated Muscle Contraction / positive regulation of ATP-dependent activity / A band / structural constituent of muscle / ventricular cardiac muscle tissue morphogenesis ...C zone / regulation of muscle filament sliding / striated muscle myosin thick filament / cardiac myofibril / regulation of striated muscle contraction / Striated Muscle Contraction / positive regulation of ATP-dependent activity / A band / structural constituent of muscle / ventricular cardiac muscle tissue morphogenesis / myosin binding / myosin heavy chain binding / ATPase activator activity / heart morphogenesis / titin binding / cardiac muscle contraction / sarcomere / actin binding / cell adhesion / identical protein binding / metal ion binding / cytosol
Similarity search - Function
MyBP-C, tri-helix bundle domain / Tri-helix bundle domain / Actins signature 1. / Actin, conserved site / Actins signature 2. / Immunoglobulin I-set / Actin/actin-like conserved site / Immunoglobulin I-set domain / Actins and actin-related proteins signature. / Actin ...MyBP-C, tri-helix bundle domain / Tri-helix bundle domain / Actins signature 1. / Actin, conserved site / Actins signature 2. / Immunoglobulin I-set / Actin/actin-like conserved site / Immunoglobulin I-set domain / Actins and actin-related proteins signature. / Actin / Actin family / Actin / Fibronectin type III domain / Fibronectin type 3 domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / ATPase, nucleotide binding domain / Immunoglobulin subtype / Immunoglobulin / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Actin, alpha cardiac muscle 1 / Myosin-binding protein C, cardiac-type
Similarity search - Component
Biological speciespig (pig) / Homo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 8.0 Å
AuthorsRisi CM / Galkin VE
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL140925 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM116790 United States
CitationJournal: J Mol Biol / Year: 2022
Title: Cryo-Electron Microscopy Reveals Cardiac Myosin Binding Protein-C M-Domain Interactions with the Thin Filament.
Authors: Cristina M Risi / Edwin Villanueva / Betty Belknap / Rachel L Sadler / Samantha P Harris / Howard D White / Vitold E Galkin /
Abstract: Cardiac myosin binding protein C (cMyBP-C) modulates cardiac contraction via direct interactions with cardiac thick (myosin) and thin (actin) filaments (cTFs). While its C-terminal domains (e.g. C8- ...Cardiac myosin binding protein C (cMyBP-C) modulates cardiac contraction via direct interactions with cardiac thick (myosin) and thin (actin) filaments (cTFs). While its C-terminal domains (e.g. C8-C10) anchor cMyBP-C to the backbone of the thick filament, its N-terminal domains (NTDs) (e.g. C0, C1, M, and C2) bind to both myosin and actin to accomplish its dual roles of inhibiting thick filaments and activating cTFs. While the positions of C0, C1 and C2 on cTF have been reported, the binding site of the M-domain on the surface of the cTF is unknown. Here, we used cryo-EM to reveal that the M-domain interacts with actin via helix 3 of its ordered tri-helix bundle region, while the unstructured part of the M-domain does not maintain extensive interactions with actin. We combined the recently obtained structure of the cTF with the positions of all the four NTDs on its surface to propose a complete model of the NTD binding to the cTF. The model predicts that the interactions of the NTDs with the cTF depend on the activation state of the cTF. At the peak of systole, when bound to the extensively activated cTF, NTDs would inhibit actomyosin interactions. In contrast, at falling Ca levels, NTDs would not compete with the myosin heads for binding to the cTF, but would rather promote formation of active cross-bridges at the adjacent regulatory units located at the opposite cTF strand. Our structural data provides a testable model of the cTF regulation by the cMyBP-C.
History
DepositionJan 14, 2022-
Header (metadata) releaseNov 23, 2022-
Map releaseNov 23, 2022-
UpdateDec 7, 2022-
Current statusDec 7, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_25918.png

Downloads & links

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Map

FileDownload / File: emd_25918.map.gz / Format: CCP4 / Size: 6.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationTHM of the regulatory M-domain and C1 Ig-domain of cMyBP-C bound to cardiac thin filament
Voxel sizeX=Y=Z: 1.345 Å
Density
Contour LevelBy AUTHOR: 0.728
Minimum - Maximum-4.0428476 - 10.977688
Average (Standard dev.)7.3340184e-13 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions8791227
Spacing9187227
CellA: 122.395004 Å / B: 117.015 Å / C: 305.315 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Cardiac thin filament decorated with C1 Ig-domain and regulatory ...

EntireName: Cardiac thin filament decorated with C1 Ig-domain and regulatory M-domain of cardiac myosin binding protein C (cMyBP-C)
Components
  • Complex: Cardiac thin filament decorated with C1 Ig-domain and regulatory M-domain of cardiac myosin binding protein C (cMyBP-C)
    • Protein or peptide: cardiac actin
    • Protein or peptide: Myosin-binding protein C, cardiac-type
    • Protein or peptide: tropomyosin model

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Supramolecule #1: Cardiac thin filament decorated with C1 Ig-domain and regulatory ...

SupramoleculeName: Cardiac thin filament decorated with C1 Ig-domain and regulatory M-domain of cardiac myosin binding protein C (cMyBP-C)
type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: all
Details: Thin filaments decorated with C1-M fragment of cMyBP-C show bound triple helix motif of the M-domain and bound C1 Ig-domain.

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Macromolecule #1: cardiac actin

MacromoleculeName: cardiac actin / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: pig (pig) / Organ: heart / Tissue: cardiac muscle
Molecular weightTheoretical: 41.830551 KDa
SequenceString: DDEETTALVC DNGSGLVKAG FAGDDAPRAV FPSIVGRPRH QGVMVGMGQK DSYVGDEAQS KRGILTLKYP IEHGIITNWD DMEKIWHHT FYNELRVAPE EHPTLLTEAP LNPKANREKM TQIMFETFNV PAMYVAIQAV LSLYASGRTT GIVLDSGDGV T HNVPIYEG ...String:
DDEETTALVC DNGSGLVKAG FAGDDAPRAV FPSIVGRPRH QGVMVGMGQK DSYVGDEAQS KRGILTLKYP IEHGIITNWD DMEKIWHHT FYNELRVAPE EHPTLLTEAP LNPKANREKM TQIMFETFNV PAMYVAIQAV LSLYASGRTT GIVLDSGDGV T HNVPIYEG YALPHAIMRL DLAGRDLTDY LMKILTERGY SFVTTAEREI VRDIKEKLCY VALDFENEMA TAASSSSLEK SY ELPDGQV ITIGNERFRC PETLFQPSFI GMESAGIHET TYNSIMKCDI DIRKDLYANN VLSGGTTMYP GIADRMQKEI TAL APSTMK IKIIAPPERK YSVWIGGSIL ASLSTFQQMW ISKQEYDEAG PSIVHRKCF

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Macromolecule #2: Myosin-binding protein C, cardiac-type

MacromoleculeName: Myosin-binding protein C, cardiac-type / type: protein_or_peptide / ID: 2 / Number of copies: 12 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.803123 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: DDPIGLFVMR PQDGEVTVGG SITFSARVAG ASLLKPPVVK WFKGKWVDLS SKVGQHLQLH DSYDRASKVY LFELHITDAQ PAFTGSYRC EVSTKDKFDC SNFNLTVHEA MGTGDLDLLS AFRRTSLAGG GRRISDSHED TGILDFSSLL KKRDSFRTPR D SKLEAPAE ...String:
DDPIGLFVMR PQDGEVTVGG SITFSARVAG ASLLKPPVVK WFKGKWVDLS SKVGQHLQLH DSYDRASKVY LFELHITDAQ PAFTGSYRC EVSTKDKFDC SNFNLTVHEA MGTGDLDLLS AFRRTSLAGG GRRISDSHED TGILDFSSLL KKRDSFRTPR D SKLEAPAE EDVWEILRQA PPSEYERIAF QYGVTDLRGM LKRLKGMRRD EKKSTAFQKK LE

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Macromolecule #3: tropomyosin model

MacromoleculeName: tropomyosin model / type: protein_or_peptide / ID: 3 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: pig (pig) / Organ: heart / Tissue: cardiac muscle
Molecular weightTheoretical: 11.507176 KDa
SequenceString: (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK) ...String:
(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statehelical array

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Sample preparation

BufferpH: 7
GridModel: PELCO Ultrathin Carbon with Lacey Carbon / Material: COPPER / Mesh: 300 / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Time: 20 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 275 K

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Electron microscopy

MicroscopeFEI TITAN 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: 3.5 µm / Nominal defocus min: 1.0 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 34.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER / Details: actin model filtered to 100A resolution
Final angle assignmentType: NOT APPLICABLE / Software - Name: IHRSR
Final reconstructionApplied symmetry - Helical parameters - Δz: 27.4 Å
Applied symmetry - Helical parameters - Δ&Phi: -166.7 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Algorithm: BACK PROJECTION / Resolution.type: BY AUTHOR / Resolution: 8.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: IHRSR / Number images used: 9710

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Atomic model buiding 1

Initial model
PDB IDChain

3mfp

chain_id: A

5k6p

chain_id: A

7jh7

chain_id: I

6g2t

chain_id: J
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-7tj7:
Cardiac thin filament decorated with C1 Ig-domain and regulatory M-domain of cardiac myosin binding protein C (cMyBP-C)

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