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- EMDB-48476: Structure of native murine cardiac thin filament variant I79N in ... -

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Entry
Database: EMDB / ID: EMD-48476
TitleStructure of native murine cardiac thin filament variant I79N in troponin T at pCa=5.8 in Ca2+-free state (lower strand)
Map data
Sample
  • Complex: Native murine cardiac thin filament variant I79N in troponin T at pCa=5.8
    • Protein or peptide: Actin, alpha cardiac muscle 1
    • Protein or peptide: Troponin C, slow skeletal and cardiac muscles
    • Protein or peptide: Troponin I, cardiac muscle
    • Protein or peptide: Isoform 6 of Troponin T, cardiac muscle
    • Protein or peptide: Tropomyosin alpha-1 chain
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: MAGNESIUM ION
Keywordsthin filament / cryo-EM / troponin / tropomyosin / muscle structure / motor protein
Function / homology
Function and homology information


actin-mediated cell contraction / positive regulation of heart rate by epinephrine / muscle thin filament tropomyosin / RHOB GTPase cycle / Formation of the dystrophin-glycoprotein complex (DGC) / regulation of systemic arterial blood pressure by ischemic conditions / Striated Muscle Contraction / troponin C binding / diaphragm contraction / RHOA GTPase cycle ...actin-mediated cell contraction / positive regulation of heart rate by epinephrine / muscle thin filament tropomyosin / RHOB GTPase cycle / Formation of the dystrophin-glycoprotein complex (DGC) / regulation of systemic arterial blood pressure by ischemic conditions / Striated Muscle Contraction / troponin C binding / diaphragm contraction / RHOA GTPase cycle / regulation of ATP-dependent activity / regulation of muscle filament sliding speed / troponin T binding / Smooth Muscle Contraction / cardiac Troponin complex / cardiac myofibril / troponin complex / actin-myosin filament sliding / regulation of muscle contraction / cardiac myofibril assembly / regulation of smooth muscle contraction / negative regulation of ATP-dependent activity / positive regulation of ATP-dependent activity / transition between fast and slow fiber / Ion homeostasis / cardiac muscle tissue morphogenesis / actomyosin structure organization / Striated Muscle Contraction / muscle filament sliding / response to metal ion / I band / regulation of cardiac muscle contraction by calcium ion signaling / ventricular cardiac muscle tissue morphogenesis / microfilament motor activity / myosin binding / regulation of heart contraction / tropomyosin binding / troponin I binding / myofibril / mesenchyme migration / striated muscle thin filament / skeletal muscle thin filament assembly / striated muscle contraction / vasculogenesis / calcium channel inhibitor activity / cardiac muscle contraction / sarcomere / filopodium / actin filament / structural constituent of cytoskeleton / Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement / intracellular calcium ion homeostasis / response to calcium ion / calcium-dependent protein binding / actin filament binding / lamellipodium / actin cytoskeleton / actin binding / heart development / cell body / response to ethanol / in utero embryonic development / hydrolase activity / response to xenobiotic stimulus / protein heterodimerization activity / protein domain specific binding / synapse / calcium ion binding / positive regulation of gene expression / negative regulation of apoptotic process / protein kinase binding / glutamatergic synapse / 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 / ATPase, nucleotide binding domain / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. / EF-hand calcium-binding domain profile. / EF-hand domain / EF-hand domain pair
Similarity search - Domain/homology
Troponin C, slow skeletal and cardiac muscles / Troponin T, cardiac muscle / Troponin I, cardiac muscle / Tropomyosin alpha-1 chain / Actin, alpha cardiac muscle 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.2 Å
AuthorsRisi CM / Galkin VE
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01HL160966 United States
CitationJournal: J Mol Cell Cardiol / Year: 2025
Title: The role of the troponin T interactions with actin in regulation of cardiac thin filament revealed by the troponin T pathogenic variant Ile79Asn.
Authors: Cristina M Risi / Maicon Landim-Vieira / Betty Belknap / P Bryant Chase / Jose R Pinto / Vitold E Galkin /
Abstract: Cardiac muscle contraction/relaxation cycle depends on the rising and falling Ca levels in sarcomeres that control the extent of interactions between myosin-based thick and actin-based thin filaments. ...Cardiac muscle contraction/relaxation cycle depends on the rising and falling Ca levels in sarcomeres that control the extent of interactions between myosin-based thick and actin-based thin filaments. Cardiac thin filament (cTF) consists of actin, tropomyosin (Tm) that regulates myosin binding to actin, and troponin complex that governs Tm position upon Ca-binding. Troponin has three subunits - Ca-binding troponin C (TnC), Tm stabilizing troponin T (TnT), and inhibitory troponin I (TnI). TnT N-terminus (TnT1) interactions with actin stabilize the inhibited state of cTF. TnC, TnI, and Tm work in concert to control actomyosin interactions. Cryo-electron microscopy (cryo-EM) provided factual structures of healthy cTF, but structures of cTF carrying missense mutations linked to human cardiomyopathy are unknown. Variant Ile79Asn in human cardiac TnT (TnT-I79N) increases myofilament Ca sensitivity and slows cross-bridge kinetics, leading to severe hypertrophic/restrictive cardiomyopathy. Here, we used TnT-I79N mutation as a tool to examine the role of TnT1 in the complex mechanism of cTF regulation. Comparison of the cryo-EM structures of murine wild type and TnT-I79N native cTFs at systolic Ca levels (pCa = 5.8) demonstrates that TnT-I79N causes 1) dissociation of the TnT1 loop from its actin interface that results in Tm release to a more activated position, 2) reduced interaction of TnI C-terminus with actin-Tm, and 3) increased frequency of Ca-bound regulatory units. Our data indicate that the TnT1 loop is a crucial element of the allosteric regulatory network that couples Tn subunits and Tm to maintain adequate cTF response to physiological Ca levels during a heartbeat.
History
DepositionDec 26, 2024-
Header (metadata) releaseJun 11, 2025-
Map releaseJun 11, 2025-
UpdateJul 2, 2025-
Current statusJul 2, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_48476.png

Downloads & links

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Map

FileDownload / File: emd_48476.map.gz / Format: CCP4 / Size: 129.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.36 Å/pix.
x 324 pix.
= 439.344 Å		1.36 Å/pix.
x 324 pix.
= 439.344 Å		1.36 Å/pix.
x 324 pix.
= 439.344 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.356 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.515
Minimum - Maximum-3.5198703 - 9.776583
Average (Standard dev.)0.0004783232 (±0.2762729)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions324324324
Spacing324324324
CellA=B=C: 439.344 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_48476_half_map_1.map
Projections & Slices
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Density Histograms

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Histogram (log scale)

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Half map: #1

Fileemd_48476_half_map_2.map
Projections & Slices
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Sample components

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Entire : Native murine cardiac thin filament variant I79N in troponin T at...

EntireName: Native murine cardiac thin filament variant I79N in troponin T at pCa=5.8
Components
  • Complex: Native murine cardiac thin filament variant I79N in troponin T at pCa=5.8
    • Protein or peptide: Actin, alpha cardiac muscle 1
    • Protein or peptide: Troponin C, slow skeletal and cardiac muscles
    • Protein or peptide: Troponin I, cardiac muscle
    • Protein or peptide: Isoform 6 of Troponin T, cardiac muscle
    • Protein or peptide: Tropomyosin alpha-1 chain
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: MAGNESIUM ION

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Supramolecule #1: Native murine cardiac thin filament variant I79N in troponin T at...

SupramoleculeName: Native murine cardiac thin filament variant I79N in troponin T at pCa=5.8
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Actin, alpha cardiac muscle 1

MacromoleculeName: Actin, alpha cardiac muscle 1 / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO
EC number: Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 42.064891 KDa
SequenceString: MCDDEETTAL VCDNGSGLVK AGFAGDDAPR AVFPSIVGRP RHQGVMVGMG QKDSYVGDEA QSKRGILTLK YPIEHGIITN WDDMEKIWH HTFYNELRVA PEEHPTLLTE APLNPKANRE KMTQIMFETF NVPAMYVAIQ AVLSLYASGR TTGIVLDSGD G VTHNVPIY ...String:
MCDDEETTAL VCDNGSGLVK AGFAGDDAPR AVFPSIVGRP RHQGVMVGMG QKDSYVGDEA QSKRGILTLK YPIEHGIITN WDDMEKIWH HTFYNELRVA PEEHPTLLTE APLNPKANRE KMTQIMFETF NVPAMYVAIQ AVLSLYASGR TTGIVLDSGD G VTHNVPIY EGYALPHAIM RLDLAGRDLT DYLMKILTER GYSFVTTAER EIVRDIKEKL CYVALDFENE MATAASSSSL EK SYELPDG QVITIGNERF RCPETLFQPS FIGMESAGIH ETTYNSIMKC DIDIRKDLYA NNVLSGGTTM YPGIADRMQK EIT ALAPST MKIKIIAPPE RKYSVWIGGS ILASLSTFQQ MWISKQEYDE AGPSIVHRKC F

UniProtKB: Actin, alpha cardiac muscle 1

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Macromolecule #2: Troponin C, slow skeletal and cardiac muscles

MacromoleculeName: Troponin C, slow skeletal and cardiac muscles / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 18.43752 KDa
SequenceString:
MDDIYKAAVE QLTEEQKNEF KAAFDIFVLG AEDGCISTKE LGKVMRMLGQ NPTPEELQEM IDEVDEDGSG TVDFDEFLVM MVRCMKDDS KGKSEEELSD LFRMFDKNAD GYIDLDELKM MLQATGETIT EDDIEELMKD GDKNNDGRID YDEFLEFMKG V E

UniProtKB: Troponin C, slow skeletal and cardiac muscles

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Macromolecule #3: Troponin I, cardiac muscle

MacromoleculeName: Troponin I, cardiac muscle / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 24.308908 KDa
SequenceString: MADESSDAAG EPQPAPAPVR RRSSANYRAY ATEPHAKKKS KISASRKLQL KTLMLQIAKQ EMEREAEERR GEKGRVLRTR CQPLELDGL GFEELQDLCR QLHARVDKVD EERYDVEAKV TKNITEIADL TQKIYDLRGK FKRPTLRRVR ISADAMMQAL L GTRAKESL ...String:
MADESSDAAG EPQPAPAPVR RRSSANYRAY ATEPHAKKKS KISASRKLQL KTLMLQIAKQ EMEREAEERR GEKGRVLRTR CQPLELDGL GFEELQDLCR QLHARVDKVD EERYDVEAKV TKNITEIADL TQKIYDLRGK FKRPTLRRVR ISADAMMQAL L GTRAKESL DLRAHLKQVK KEDIEKENRE VGDWRKNIDA LSGMEGRKKK FEG

UniProtKB: Troponin I, cardiac muscle

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Macromolecule #4: Isoform 6 of Troponin T, cardiac muscle

MacromoleculeName: Isoform 6 of Troponin T, cardiac muscle / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 34.660332 KDa
SequenceString: MSDIEEVVEE YEEEEQEEAA VEEQEEAAEE DAEAEAETEE TRAEEDEEEE EAKEAEDGPM EESKPKPRSF MPNLVPPKNP DGERVDFDD IHRKRMEKDL NELQALIEAH FENRKKEEEE LVSLKDRIER RRAERAEQQR IRNEREKERQ NRLAEERARR E EEENRRKA ...String:
MSDIEEVVEE YEEEEQEEAA VEEQEEAAEE DAEAEAETEE TRAEEDEEEE EAKEAEDGPM EESKPKPRSF MPNLVPPKNP DGERVDFDD IHRKRMEKDL NELQALIEAH FENRKKEEEE LVSLKDRIER RRAERAEQQR IRNEREKERQ NRLAEERARR E EEENRRKA EDEARKKKAL SNMMHFGGYI QKQAQTERKS GKRQTEREKK KKILAERRKV LAIDHLNEDQ LREKAKELWQ SI YNLEAEK FDLQEKFKQQ KYEINVLRNR INDNQKVSKT RGKAKVTGRW K

UniProtKB: Troponin T, cardiac muscle

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Macromolecule #5: Tropomyosin alpha-1 chain

MacromoleculeName: Tropomyosin alpha-1 chain / type: protein_or_peptide / ID: 5 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 32.735609 KDa
SequenceString: MDAIKKKMQM LKLDKENALD RAEQAEADKK AAEDRSKQLE DELVSLQKKL KGTEDELDKY SEALKDAQEK LELAEKKATD AEADVASLN RRIQLVEEEL DRAQERLATA LQKLEEAEKA ADESERGMKV IESRAQKDEE KMEIQEIQLK EAKHIAEDAD R KYEEVARK ...String:
MDAIKKKMQM LKLDKENALD RAEQAEADKK AAEDRSKQLE DELVSLQKKL KGTEDELDKY SEALKDAQEK LELAEKKATD AEADVASLN RRIQLVEEEL DRAQERLATA LQKLEEAEKA ADESERGMKV IESRAQKDEE KMEIQEIQLK EAKHIAEDAD R KYEEVARK LVIIESDLER AEERAELSEG KCAELEEELK TVTNNLKSLE AQAEKYSQKE DKYEEEIKVL SDKLKEAETR AE FAERSVT KLEKSIDDLE DELYAQKLKY KAISEELDHA LNDMTSI

UniProtKB: Tropomyosin alpha-1 chain

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Macromolecule #6: ADENOSINE-5'-DIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-DIPHOSPHATE / type: ligand / ID: 6 / Number of copies: 6 / Formula: ADP
Molecular weightTheoretical: 427.201 Da
Chemical component information

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

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Macromolecule #7: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 7 / Number of copies: 6 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 7
GridModel: EMS Lacey Carbon / Material: COPPER / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 45 sec.
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number real images: 17361 / Average electron dose: 34.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.5 µm / Nominal defocus min: 0.5 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 7615631
CTF correctionSoftware - Name: RELION / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7ko4


Details: filtered to 30A
Final reconstructionAlgorithm: BACK PROJECTION / Resolution.type: BY AUTHOR / Resolution: 5.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Details: filtered to 7 Angstroms / Number images used: 51543
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final 3D classificationNumber classes: 5 / Software - Name: RELION
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChain

7ko4

source_name: PDB, initial_model_type: experimental model

7utl

source_name: PDB, initial_model_type: experimental model

8uyd

source_name: PDB, initial_model_type: experimental model

8dd0

source_name: PDB, initial_model_type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-9moo:
Structure of native murine cardiac thin filament variant I79N in troponin T at pCa=5.8 in Ca2+-free state (lower strand)

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