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- PDB-7uti: ALTERNATIVE MODELING OF TROPOMYOSIN IN HUMAN CARDIAC THIN FILAMEN... -

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Basic information

Entry
Database: PDB / ID: 7uti
TitleALTERNATIVE MODELING OF TROPOMYOSIN IN HUMAN CARDIAC THIN FILAMENT IN THE CALCIUM BOUND STATE
Components
  • Actin, alpha skeletal muscle
  • Isoform 6 of Troponin T, cardiac muscle
  • Tropomyosin alpha-1 chain
  • Troponin C, slow skeletal and cardiac muscles
  • Troponin I, cardiac muscle
KeywordsCONTRACTILE PROTEIN / TROPONIN / TROPOMYOSIN / ACTIN / THIN FILEMENT / MUSCLE / CONTRACTILE
Function / homology
Function and homology information


positive regulation of heart rate by epinephrine / muscle thin filament tropomyosin / regulation of systemic arterial blood pressure by ischemic conditions / troponin C binding / diaphragm contraction / regulation of muscle filament sliding speed / troponin T binding / cardiac Troponin complex / cardiac myofibril / negative regulation of ATP-dependent activity ...positive regulation of heart rate by epinephrine / muscle thin filament tropomyosin / regulation of systemic arterial blood pressure by ischemic conditions / troponin C binding / diaphragm contraction / regulation of muscle filament sliding speed / troponin T binding / cardiac Troponin complex / cardiac myofibril / negative regulation of ATP-dependent activity / troponin complex / regulation of muscle contraction / bleb / ruffle organization / positive regulation of ATP-dependent activity / Striated Muscle Contraction / muscle filament sliding / sarcomere organization / regulation of heart contraction / regulation of cardiac muscle contraction by calcium ion signaling / response to metal ion / regulation of smooth muscle contraction / cardiac muscle cell contraction / heart contraction / cytoskeletal motor activator activity / structural constituent of muscle / ventricular cardiac muscle tissue morphogenesis / myosin heavy chain binding / negative regulation of vascular associated smooth muscle cell migration / tropomyosin binding / actin filament bundle / troponin I binding / filamentous actin / mesenchyme migration / negative regulation of vascular associated smooth muscle cell proliferation / skeletal muscle myofibril / striated muscle thin filament / vasculogenesis / actin filament bundle assembly / skeletal muscle thin filament assembly / actin monomer binding / Smooth Muscle Contraction / skeletal muscle fiber development / cardiac muscle contraction / calcium channel inhibitor activity / positive regulation of stress fiber assembly / skeletal muscle contraction / cytoskeletal protein binding / cytoskeleton organization / Ion homeostasis / actin filament polymerization / stress fiber / titin binding / positive regulation of cell adhesion / negative regulation of cell migration / actin filament organization / wound healing / sarcomere / actin filament / filopodium / cellular response to reactive oxygen species / response to calcium ion / intracellular calcium ion homeostasis / Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement / ruffle membrane / structural constituent of cytoskeleton / calcium-dependent protein binding / heart development / actin filament binding / regulation of cell shape / lamellipodium / actin binding / cell body / cytoskeleton / protein heterodimerization activity / protein domain specific binding / hydrolase activity / positive regulation of gene expression / calcium ion binding / protein kinase binding / magnesium ion binding / protein homodimerization activity / ATP binding / identical protein binding / cytosol / cytoplasm
Similarity search - Function
Troponin T / Troponin I residues 1-32 / Troponin I residues 1-32 / : / Troponin / Troponin domain superfamily / Troponin / Tropomyosins signature. / Tropomyosin / Tropomyosin ...Troponin T / Troponin I residues 1-32 / Troponin I residues 1-32 / : / Troponin / Troponin domain superfamily / Troponin / Tropomyosins signature. / Tropomyosin / Tropomyosin / EF-hand domain pair / : / Actins signature 1. / Actin, conserved site / Actins signature 2. / Actin/actin-like conserved site / Actins and actin-related proteins signature. / Actin / Actin family / Actin / EF-hand domain pair / EF-hand, calcium binding motif / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. / ATPase, nucleotide binding domain / EF-hand calcium-binding domain profile. / EF-hand domain / EF-hand domain pair
Similarity search - Domain/homology
ADENOSINE-5'-DIPHOSPHATE / Tropomyosin alpha-1 chain / Troponin I, cardiac muscle / Troponin T, cardiac muscle / Troponin C, slow skeletal and cardiac muscles / Actin, alpha skeletal muscle
Similarity search - Component
Biological speciesHomo sapiens (human)
Oryctolagus cuniculus (rabbit)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.8 Å
AuthorsRynkiewicz, M.J. / Pavadai, E. / Lehman, W.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01HL036153 United States
Citation
Journal: Biophys J / Year: 2020
Title: Protein-Protein Docking Reveals Dynamic Interactions of Tropomyosin on Actin Filaments.
Authors: Elumalai Pavadai / William Lehman / Michael J Rynkiewicz /
Abstract: Experimental approaches such as fiber diffraction and cryo-electron microscopy reconstruction have defined regulatory positions of tropomyosin on actin but have not, as yet, succeeded at determining ...Experimental approaches such as fiber diffraction and cryo-electron microscopy reconstruction have defined regulatory positions of tropomyosin on actin but have not, as yet, succeeded at determining key atomic-level contacts between these proteins or fully substantiated the dynamics of their interactions at a structural level. To overcome this deficiency, we have previously employed computational approaches to deduce global dynamics of thin filament components by energy landscape determination and molecular dynamics simulations. Still, these approaches remain computationally challenging for any complex and large macromolecular assembly like the thin filament. For example, tropomyosin cable wrapping around actin of thin filaments features both head-to-tail polymeric interactions and local twisting, both of which depart from strict superhelical symmetry. This produces a complex energy surface that is difficult to model and thus to evaluate globally. Therefore, at this stage of our understanding, assessing global molecular dynamics can prove to be inherently impractical. As an alternative, we adopted a "divide and conquer" protocol to investigate actin-tropomyosin interactions at an atomistic level. Here, we first employed unbiased protein-protein docking tools to identify binding specificity of individual tropomyosin pseudorepeat segments over the actin surface. Accordingly, tropomyosin "ligand" segments were rotated and translated over potential "target" binding sites on F-actin where the corresponding interaction energetics of billions of conformational poses were ranked by the programs PIPER and ClusPro. These data were used to assess favorable interactions and then to rebuild models of seamless and continuous tropomyosin cables over the F-actin substrate, which were optimized further by flexible fitting routines and molecular dynamics. The models generated azimuthally distinct regulatory positions for tropomyosin cables along thin filaments on actin dominated by stereo-specific head-to-tail overlap linkage. The outcomes are in good agreement with current cryo-electron microscopy topology and consistent with long-thought residue-to-residue interactions between actin and tropomyosin.
#1: Journal: Nat Commun / Year: 2020
Title: Cardiac muscle thin filament structures reveal calcium regulatory mechanism.
Authors: Yurika Yamada / Keiichi Namba / Takashi Fujii /
Abstract: Contraction of striated muscles is driven by cyclic interactions of myosin head projecting from the thick filament with actin filament and is regulated by Ca released from sarcoplasmic reticulum. ...Contraction of striated muscles is driven by cyclic interactions of myosin head projecting from the thick filament with actin filament and is regulated by Ca released from sarcoplasmic reticulum. Muscle thin filament consists of actin, tropomyosin and troponin, and Ca binding to troponin triggers conformational changes of troponin and tropomyosin to allow actin-myosin interactions. However, the structural changes involved in this regulatory mechanism remain unknown. Here we report the structures of human cardiac muscle thin filament in the absence and presence of Ca by electron cryomicroscopy. Molecular models in the two states built based on available crystal structures reveal the structures of a C-terminal region of troponin I and an N-terminal region of troponin T in complex with the head-to-tail junction of tropomyosin together with the troponin core on actin filament. Structural changes of the thin filament upon Ca binding now reveal the mechanism of Ca regulation of muscle contraction.
History
DepositionApr 27, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 21, 2022Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
C: Actin, alpha skeletal muscle
D: Actin, alpha skeletal muscle
E: Actin, alpha skeletal muscle
F: Actin, alpha skeletal muscle
G: Actin, alpha skeletal muscle
H: Actin, alpha skeletal muscle
I: Actin, alpha skeletal muscle
J: Actin, alpha skeletal muscle
K: Actin, alpha skeletal muscle
L: Actin, alpha skeletal muscle
M: Actin, alpha skeletal muscle
N: Actin, alpha skeletal muscle
O: Actin, alpha skeletal muscle
P: Actin, alpha skeletal muscle
Q: Actin, alpha skeletal muscle
R: Actin, alpha skeletal muscle
e: Tropomyosin alpha-1 chain
f: Tropomyosin alpha-1 chain
W: Tropomyosin alpha-1 chain
b: Tropomyosin alpha-1 chain
X: Isoform 6 of Troponin T, cardiac muscle
Y: Isoform 6 of Troponin T, cardiac muscle
V: Troponin I, cardiac muscle
U: Troponin C, slow skeletal and cardiac muscles
i: Tropomyosin alpha-1 chain
j: Tropomyosin alpha-1 chain
g: Tropomyosin alpha-1 chain
h: Tropomyosin alpha-1 chain
c: Isoform 6 of Troponin T, cardiac muscle
d: Isoform 6 of Troponin T, cardiac muscle
a: Troponin I, cardiac muscle
Z: Troponin C, slow skeletal and cardiac muscles
hetero molecules


Theoretical massNumber of molelcules
Total (without water)1,167,13570
Polymers1,159,67132
Non-polymers7,46538
Water00
1


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

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Components

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Protein , 5 types, 32 molecules CDEFGHIJKLMNOPQRefWbijghXYcdVaUZ

#1: Protein
Actin, alpha skeletal muscle / Alpha-actin-1


Mass: 42109.973 Da / Num. of mol.: 16 / Source method: isolated from a natural source / Source: (natural) Oryctolagus cuniculus (rabbit) / References: UniProt: P68135
#2: Protein
Tropomyosin alpha-1 chain / Alpha-tropomyosin / Tropomyosin-1


Mass: 32789.656 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TPM1, C15orf13, TMSA / Production host: Escherichia coli (E. coli) / References: UniProt: P09493
#3: Protein
Isoform 6 of Troponin T, cardiac muscle / TnTc / Cardiac muscle troponin T / cTnT


Mass: 34659.387 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TNNT2 / Production host: Escherichia coli (E. coli) / References: UniProt: P45379
#4: Protein Troponin I, cardiac muscle / Cardiac troponin I


Mass: 24058.686 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TNNI3, TNNC1 / Production host: Escherichia coli (E. coli) / References: UniProt: P19429
#5: Protein Troponin C, slow skeletal and cardiac muscles / TN-C


Mass: 18419.482 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TNNC1, TNNC / Production host: Escherichia coli (E. coli) / References: UniProt: P63316

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Non-polymers , 3 types, 38 molecules

#6: Chemical
ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
#7: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: Mg
#8: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Ca

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Details

Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: HUMAN CARDIAC THIN FILAMENT IN THE CALCIUM BOUND STATE
Type: COMPLEX / Entity ID: #1-#5 / Source: MULTIPLE SOURCES
Buffer solutionpH: 7.5
SpecimenConc.: 0.05 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: CARDIAC MUSCLE THIN FILAMENT IN THE CALCIUM BOUND STATE; ACTIN, ALPHA SKELETAL MUSCLE; TROPOMYOSIN, TROPONIN
Specimen supportGrid material: MOLYBDENUM / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: LEICA EM GP / Cryogen name: ETHANE / Humidity: 80 %

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Electron microscopy imaging

MicroscopyModel: JEOL CRYO ARM 200
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 700 nm
Image recordingElectron dose: 65 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of real images: 2880

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Processing

EM software
IDNameCategory
2JADASimage acquisition
13RELION3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 23374 / Symmetry type: POINT

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