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- PDB-7tit: Cardiac thin filament decorated with regulatory M-domain of cardi... -

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Basic information

Entry
Database: PDB / ID: 7tit
TitleCardiac thin filament decorated with regulatory M-domain of cardiac myosin binding protein C
Components
  • Myosin-binding protein C, cardiac-type
  • cardiac actin
  • tropomyosin model
KeywordsMOTOR PROTEIN / cardiac contraction regulator / muscle protein
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 speciesHomo sapiens (human)
Sus scrofa (pig)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 8 Å
AuthorsRisi, C.M. / Galkin, V.E.
Funding support United States, 2items
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, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 23, 2022Provider: repository / Type: Initial release
Revision 1.1Dec 7, 2022Group: Database references / Refinement description / Category: citation / pdbx_initial_refinement_model / Item: _citation.journal_volume / _citation.title
Revision 2.0Mar 22, 2023Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Source and taxonomy / Structure summary
Category: atom_site / em_software ...atom_site / em_software / entity_src_nat / pdbx_contact_author / pdbx_validate_close_contact
Item: _entity_src_nat.pdbx_beg_seq_num / _entity_src_nat.pdbx_end_seq_num
Description: Atoms with unrealistic or zero occupancies / Provider: author / Type: Coordinate replacement

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: cardiac actin
B: cardiac actin
C: cardiac actin
D: cardiac actin
E: cardiac actin
F: cardiac actin
G: Myosin-binding protein C, cardiac-type
H: Myosin-binding protein C, cardiac-type
I: Myosin-binding protein C, cardiac-type
J: Myosin-binding protein C, cardiac-type
K: Myosin-binding protein C, cardiac-type
L: Myosin-binding protein C, cardiac-type
M: tropomyosin model
N: tropomyosin model
O: tropomyosin model
P: tropomyosin model


Theoretical massNumber of molelcules
Total (without water)445,83116
Polymers445,83116
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
cardiac actin


Mass: 41830.551 Da / Num. of mol.: 6 / Source method: isolated from a natural source / Source: (natural) Sus scrofa (pig) / Organ: heart / Tissue: cardiac muscle / References: UniProt: A0A4X1UMF3
#2: Protein
Myosin-binding protein C, cardiac-type / Cardiac MyBP-C / C-protein / cardiac muscle isoform


Mass: 24803.123 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Details: only triple helix motif from C1-M construct bound to thin filament is visible in the map and contained in the model
Source: (gene. exp.) Homo sapiens (human) / Gene: MYBPC3 / Production host: Escherichia coli (E. coli) / References: UniProt: Q14896
#3: Protein
tropomyosin model


Mass: 11507.176 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Source: (natural) Sus scrofa (pig) / Organ: heart / Tissue: cardiac muscle

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: HELICAL ARRAY / 3D reconstruction method: helical reconstruction

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Sample preparation

ComponentName: Complex of cardiac thin filament with C1-M fragment of cardiac myosin binding protein C (cMyBP-C)
Type: COMPLEX
Details: Only triple helix motif of the M-domain is visible in the map. C1 domain is not bound and hence not visible in the map.
Entity ID: all / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Buffer solutionpH: 7
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: PELCO Ultrathin Carbon with Lacey Carbon
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 275 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 3500 nm / Nominal defocus min: 1000 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 34 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
EM software
IDNameVersionCategory
2EPUimage acquisition
4CTFFIND4CTF correction
7PHENIXmodel fitting
9IHRSRinitial Euler assignment
10IHRSRfinal Euler assignment
11SPIDERclassification
12IHRSR3D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -166.7 ° / Axial rise/subunit: 27.4 Å / Axial symmetry: C1
3D reconstructionResolution: 8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 14282 / Algorithm: BACK PROJECTION / Symmetry type: HELICAL
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model building
IDPDB-IDPdb chain-ID 3D fitting-ID
13MFP

3mfp

A1
25K6P

5k6p

A1
37JH7

7jh7

I1
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0122682
ELECTRON MICROSCOPYf_angle_d1.22630816
ELECTRON MICROSCOPYf_dihedral_angle_d15.8713266
ELECTRON MICROSCOPYf_chiral_restr0.0543516
ELECTRON MICROSCOPYf_plane_restr0.0114040

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