Affinage

TNNC1

Troponin I, cardiac muscle · UniProt P19429

Length
210 aa
Mass
24.0 kDa
Annotated
2026-06-10
22 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TNNC1 encodes cardiac troponin C, the Ca2+-sensing subunit of the thin-filament troponin complex that couples cytosolic Ca2+ flux to sarcomeric contraction: its C-terminal globular domain holds two high-affinity Ca2+/Mg2+ sites that are constitutively occupied to anchor the complex, while its regulatory N-domain carries a single low-affinity Ca2+ site whose occupancy drives an open conformation that engages the troponin I switch region and relieves actin inhibition to permit contraction (PMID:26232335). Disease-associated missense variants act through opposite effects on this Ca2+ switch: HCM mutations (A8V, A31S, L29Q, and others) raise the affinity of regulatory site II for both Ca2+ and Mg2+, increasing myofilament Ca2+ sensitivity of force development (PMID:18572189, PMID:22815480, PMID:35838319), whereas DCM-associated variants (Y5H, M103I) lower Ca2+ sensitivity and additionally blunt PKA-mediated modulation of the thin filament (PMID:21832052). An A8V knock-in mouse reproduces this gain-of-function, producing prolonged Ca2+ and contractile transients, slowed relaxation, diastolic dysfunction, and cardiac remodeling in vivo (PMID:26304555). Beyond striated muscle, TNNC1 functions in cancer-cell signaling: it is induced downstream of MFAP5–FAK–CREB signaling to promote ovarian cancer motility (PMID:25277212), drives AKT/GSK-3β-dependent EMT and F-actin dynamics (PMID:33592378), and is transcriptionally activated by E2F1 under control of the KDM5D demethylase (PMID:38504588), with both tumor-promoting and tumor-suppressive roles reported across tissue contexts (PMID:32638704).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1997 Medium

    Establishing the chromosomal location of human TNNC1 provided the genomic anchor needed to link the gene to inherited disease loci.

    Evidence Somatic cell hybrid and radiation hybrid panel mapping placing TNNC1 on chromosome 3p

    PMID:9365790

    Open questions at the time
    • Does not address protein function or regulation
    • No disease association established at this stage
  2. 2008 High

    The question of how HCM mutations alter contraction was answered by showing they confer a myofilament-level gain of function via increased Ca2+ sensitivity.

    Evidence Recombinant mutant cTnC reconstituted into skinned cardiac fibers with Ca2+-force and actomyosin ATPase readouts

    PMID:18572189

    Open questions at the time
    • Mechanism of the affinity change at the atomic level not resolved
    • Whether all listed variants act identically unclear (E134D showed no effect)
  3. 2011 High

    DCM variants were shown to act in the opposite direction from HCM variants, decreasing Ca2+ sensitivity and impairing PKA modulation, establishing a bidirectional disease mechanism.

    Evidence Skinned fiber reconstitution, actomyosin ATPase, circular dichroism, and PKA phosphorylation assays with recombinant mutants

    PMID:21832052

    Open questions at the time
    • Structural basis linking helical content loss to functional change not defined
    • In vivo cardiac consequences not tested
  4. 2012 High

    The A31S study traced increased Ca2+ sensitivity directly to elevated Ca2+ affinity at successive levels of thin-filament assembly, connecting the molecular defect to contractile output.

    Evidence Ca2+ binding by fluorescence, skinned fiber force, actomyosin ATPase, and CD across isolated cTnC, troponin, and thin filament

    PMID:22815480

    Open questions at the time
    • No in vivo validation in this study
    • Maximal force unaffected, leaving downstream remodeling triggers unexplained
  5. 2015 High

    An A8V knock-in mouse established that increased thin-filament Ca2+ affinity is sufficient to cause diastolic dysfunction and cardiac remodeling in vivo, moving the mechanism from the test tube to the whole heart.

    Evidence Knock-in mouse with echocardiography, pressure-volume studies, intact cardiomyocyte Ca2+ transients, and diazo-2 flash photolysis

    PMID:26304555

    Open questions at the time
    • Therapeutic reversal of the phenotype not tested
    • Generalizability to other HCM variants not addressed
  6. 2021 Medium

    The G34S variant extended the disease logic beyond simple Ca2+ affinity, showing that disrupted inter-subunit and actin interactions destabilize the thin filament and engage protein quality control, and that troponin-targeting drugs can partially correct it.

    Evidence Skinned cardiomyocyte/fiber assays, reconstituted thin filament and interaction assays, patient myocardial tissue, and levosimendan/EGCg treatment

    PMID:34502534

    Open questions at the time
    • Single study with limited patient tissue
    • Drug effects in vitro only, no in vivo efficacy
  7. 2022 Medium

    Quantitative thermodynamics resolved that HCM variants raise affinity for both Ca2+ and Mg2+ at site II, introducing Mg2+ competition as a modulator of contractile Ca2+ sensitivity.

    Evidence Isothermal titration calorimetry and thermodynamic integration simulations on recombinant mutants

    PMID:35838319

    Open questions at the time
    • Single-lab measurement
    • Physiological relevance of Mg2+ competition not tested in cells or in vivo
  8. 2024 Medium

    Beyond contraction, TNNC1 was placed in cancer signaling networks: it is induced via MFAP5/FAK/CREB and E2F1/KDM5D axes and feeds AKT-driven EMT and autophagy, with context-dependent oncogenic and tumor-suppressive roles.

    Evidence siRNA/CRISPR perturbation, EMT and AKT/GSK-3β marker blots, ChIP and luciferase reporter for E2F1 promoter binding, and xenograft models across ovarian, lung, and hepatocellular cancers

    PMID:25277212 PMID:32638704 PMID:33592378 PMID:38504588

    Open questions at the time
    • Direction of effect differs between cancer types and is unreconciled
    • Direct molecular activity of TNNC1 in non-muscle cells not defined
    • How a sarcomeric Ca2+ sensor functions in cancer signaling is mechanistically unexplained

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular basis for TNNC1's non-muscle, cancer-associated functions remains unresolved.
  • No biochemical activity or binding partner established for TNNC1 outside the troponin complex
  • Reconciliation of tumor-promoting versus tumor-suppressive roles lacking
  • Subcellular localization in cancer cells not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0140299 molecular sensor activity 3 GO:0005198 structural molecule activity 2
Localization
GO:0005856 cytoskeleton 2
Pathway
R-HSA-397014 Muscle contraction 3 R-HSA-162582 Signal Transduction 2
Partners
ACTC1E2F1MFAP5TNNI3
Complex memberships
cardiac thin filamenttroponin complex

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 Cardiac troponin C (cTnC) is composed of two globular EF-hand domains connected by a flexible linker. The C-domain (cCTnC) contains two high-affinity Ca2+/Mg2+-binding sites that are constitutively occupied under physiologic conditions, stabilizing an open conformation anchored to the troponin complex. The regulatory N-domain (cNTnC) contains a single low-affinity Ca2+-binding site; Ca2+ binding favors an open conformation that engages the switch region of troponin I, releasing inhibitory regions of troponin I from actin to allow contraction. Review synthesizing structural and functional studies (NMR, crystallography, in vitro biochemical assays, mutagenesis) Gene High 26232335
2008 HCM-associated missense mutations in TNNC1 (A8V, C84Y, D145E) increase Ca2+ sensitivity of force development and force recovery in reconstituted skinned fiber assays, consistent with a gain-of-function mechanism at the myofilament level. E134D showed no change in these parameters. Recombinant mutant cTnC proteins reconstituted into skinned cardiac fibers; Ca2+-force relationship measurements; actomyosin ATPase assays Journal of molecular and cellular cardiology High 18572189
2011 DCM-associated TNNC1 rare variants (Y5H, M103I) decrease Ca2+ sensitivity of force development in skinned fiber reconstitution assays, opposite to HCM mutations. M103I abolishes and Y5H diminishes the effects of PKA phosphorylation on Ca2+ sensitivity, and M103I decreases actomyosin ATPase activation at high Ca2+. CD spectroscopy showed that the mutants (except I148V in Ca2+/Mg2+ condition) reduced α-helical content, indicating structural perturbation. Recombinant mutant cTnC proteins reconstituted into porcine papillary skinned fibers; actomyosin ATPase assays; circular dichroism spectroscopy; PKA phosphorylation experiments The Journal of biological chemistry High 21832052
2012 The TNNC1-A31S mutation increases Ca2+ affinity in isolated cTnC, in the troponin complex, in the thin filament, and (to a lesser degree) in the thin filament with myosin subfragment 1. Reconstituted skinned fibers showed increased Ca2+ sensitivity of force development without affecting maximal force, and 50% mutant:50% WT actomyosin ATPase assays showed intermediate Ca2+ sensitivity. Circular dichroism indicated no global secondary structure change. Skinned fiber reconstitution; actomyosin ATPase assay; fluorescence Ca2+ binding studies; circular dichroism spectroscopy The Journal of biological chemistry High 22815480
2015 Knock-in mice expressing the TNNC1-A8V mutation show dose-dependent increases in Ca2+ sensitivity of contraction in skinned fibers, reduced diastolic sarcomere length, increased shortening, prolonged Ca2+ and contractile transients in intact cardiomyocytes, and slower relaxation on flash photolysis of diazo-2. These changes lead to diastolic dysfunction and cardiac remodeling in vivo, establishing that the A8V mutation increases Ca2+-binding affinity of the thin filament. Knock-in mouse model; echocardiography; pressure-volume studies; skinned fiber Ca2+-force relationships; liquid chromatography-mass spectrometry for myofilament incorporation; intact cardiomyocyte Ca2+ transients; flash photolysis of diazo-2 Circulation. Cardiovascular genetics High 26304555
2022 HCM-associated TNNC1 variants (A8V, L29Q, A31S) elevate the binding affinity of cTnC for both Ca2+ and Mg2+ at the regulatory site II of the N-domain. Variants adjacent to the EF-hand motif of site II (L48Q, Q50R, C84Y) have a more significant effect on binding affinity and thermodynamics. Physiological concentrations of Mg2+ may compete with Ca2+ at site II, modulating Ca2+ sensitivity of contraction. Isothermal titration calorimetry (ITC) with recombinant mutant cTnC proteins; thermodynamic integration (TI) computational simulations The FEBS journal Medium 35838319
2021 The de novo TNNC1-G34S mutation impairs Ca2+-regulated force production in skinned cardiomyocytes and fibers. The mutant cTnC shows altered interaction with actin and disrupted inter-subunit interactions within the troponin complex, and compromises the structural integrity of reconstituted thin filaments. The protein quality control system is affected in patient myocardial tissue. Troponin-targeting agents levosimendan and EGCg partially stabilized thin filament structure and ameliorated contractile function in vitro. Skinned cardiomyocytes and fibers; reconstituted thin filament assays; protein interaction assays; patient myocardial tissue analysis; drug treatment experiments International journal of molecular sciences Medium 34502534
2014 In ovarian cancer cells, MFAP5 stromal signaling activates FAK, which in turn activates CREB, leading to upregulation of TNNC1; this FAK/CREB/TNNC1 axis mediates MFAP5-driven ovarian cancer cell motility and invasion. Knockdown of MFAP5 with siRNA nanoparticles decreased tumour growth and metastasis in vivo. siRNA knockdown; functional migration/invasion assays; in vivo mouse tumour model; pathway inhibition experiments Nature communications Medium 25277212
2021 TNNC1 knockout in SKOV-3 ovarian cancer cells (via CRISPR/Cas9) reduces proliferation, colony formation, migration, and invasion. TNNC1 loss decreases phosphorylated AKT (Ser-473, Thr-308) and inactive GSK-3β, downregulates SNAIL and SLUG (relocating them to cytoplasm), decreases N-cadherin and vimentin while increasing E-cadherin, and suppresses F-actin polymerization, indicating that TNNC1 promotes EMT and actin dynamics in cancer cells. CRISPR/Cas9 knockout; western blot for EMT markers and AKT/GSK-3β phosphorylation; migration/invasion assays; F-actin staining Biochemical and biophysical research communications Medium 33592378
2020 In lung adenocarcinoma cells, ectopic TNNC1 expression inhibits KRASG12D-mediated anchorage-independent growth and colony formation, induces DNA damage, cell cycle arrest, and apoptosis. KRAS suppression enhances TNNC1 expression, suggesting TNNC1 acts downstream of KRAS as a tumor suppressor. RNAi-mediated TNNC1 knockdown enhances in vitro invasiveness. Ectopic TNNC1 overexpression; siRNA knockdown; colony formation assay; anchorage-independent growth assay; flow cytometry for apoptosis/cell cycle; DNA damage assay Molecules and cells Medium 32638704
2020 TNNC1 promotes gemcitabine resistance in non-small cell lung cancer by activating cytoprotective autophagy. FOXO3 negatively regulates this axis: silencing FOXO3 in GEM-resistant cells rescues autophagy weakened by TNNC1 knockdown. Blocking autophagy with 3-methyladenine restores chemotherapy sensitivity. siRNA knockdown; forced overexpression; flow cytometry; LC3 punctate assay; 3-methyladenine autophagy inhibition; FOXO3 loss-of-function epistasis Medical science monitor Low 32946432
2024 KDM5D demethylase suppresses H3K4me3 at the E2F1 promoter, reducing E2F1 expression. E2F1 transcription factor binds the TNNC1 promoter and activates TNNC1 transcription (confirmed by ChIP and dual luciferase reporter assay). KDM5D overexpression thus reduces TNNC1 expression in HCC cells through the KDM5D/E2F1/TNNC1 axis, inhibiting cancer cell proliferation, migration, and invasion. ChIP assay for H3K4me3 and E2F1 promoter occupancy; dual luciferase reporter assay; western blot; overexpression/knockdown; in vivo nude mouse xenograft Antioxidants & redox signaling Medium 38504588
2020 LukS-PV downregulates TNNC1 expression in HCC cells and inhibits HCC cell migration. LukS-PV inhibits phosphorylation of PI3K/AKT by targeting TNNC1, placing TNNC1 upstream of PI3K/AKT in regulating HCC cell migration. Scratch assay; western blot; RNA sequencing; quantitative proteomics; KEGG/GSEA pathway analysis; siRNA/overexpression OncoTargets and therapy Low 33116603
1997 The human TNNC1 gene was mapped to the short arm of chromosome 3, between markers D3S3118 and GCT4B10, by somatic cell hybrid and radiation hybrid panel analysis. Somatic cell hybrid PCR analysis; Genebridge4 radiation hybrid panel mapping Annals of human genetics Medium 9365790

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Coding sequence rare variants identified in MYBPC3, MYH6, TPM1, TNNC1, and TNNI3 from 312 patients with familial or idiopathic dilated cardiomyopathy. Circulation. Cardiovascular genetics 199 20215591
2014 Calcium-dependent FAK/CREB/TNNC1 signalling mediates the effect of stromal MFAP5 on ovarian cancer metastatic potential. Nature communications 113 25277212
2008 Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C. Journal of molecular and cellular cardiology 106 18572189
2015 Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs. Gene 99 26232335
2012 A mutation in TNNC1-encoded cardiac troponin C, TNNC1-A31S, predisposes to hypertrophic cardiomyopathy and ventricular fibrillation. The Journal of biological chemistry 51 22815480
2011 Functional characterization of TNNC1 rare variants identified in dilated cardiomyopathy. The Journal of biological chemistry 49 21832052
2015 In Vivo Analysis of Troponin C Knock-In (A8V) Mice: Evidence that TNNC1 Is a Hypertrophic Cardiomyopathy Susceptibility Gene. Circulation. Cardiovascular genetics 38 26304555
2016 Evidence for troponin C (TNNC1) as a gene for autosomal recessive restrictive cardiomyopathy with fatal outcome in infancy. American journal of medical genetics. Part A 37 27604170
2011 Novel frameshift mutation in Troponin C ( TNNC1) associated with hypertrophic cardiomyopathy and sudden death. Cardiology in the young 23 21262074
2020 Characterization of TNNC1 as a Novel Tumor Suppressor of Lung Adenocarcinoma. Molecules and cells 19 32638704
1995 Mapping TNNC1, the gene that encodes cardiac troponin I in the human and the mouse. Genomics 15 8825654
2020 TNNC1 Reduced Gemcitabine Sensitivity of Nonsmall-Cell Lung Cancer by Increasing Autophagy. Medical science monitor : international medical journal of experimental and clinical research 13 32946432
2020 LukS-PV Inhibits Hepatocellular Carcinoma Cells Migration via the TNNC1/PI3K/AKT Axis. OncoTargets and therapy 12 33116603
2021 De Novo Missense Mutations in TNNC1 and TNNI3 Causing Severe Infantile Cardiomyopathy Affect Myofilament Structure and Function and Are Modulated by Troponin Targeting Agents. International journal of molecular sciences 11 34502534
2024 Paeonol upregulates expression of tumor suppressors TNNC1 and SCARA5, exerting anti-tumor activity in non-small cell lung cancer cells. Naunyn-Schmiedeberg's archives of pharmacology 8 38265681
2021 TNNC1 knockout reverses metastatic potential of ovarian cancer cells by inactivating epithelial-mesenchymal transition and suppressing F-actin polymerization. Biochemical and biophysical research communications 8 33592378
2024 Histone demethylase KDM5D represses the proliferation, migration and invasion of hepatocellular carcinoma through the E2F1/TNNC1 axis. Antioxidants & redox signaling 6 38504588
2022 The effect of Mg2+ on Ca2+ binding to cardiac troponin C in hypertrophic cardiomyopathy associated TNNC1 variants. The FEBS journal 6 35838319
1997 Assignment of the human cardiac/slow skeletal muscle troponin C gene (TNNC1) between D3S3118 and GCT4B10 on the short arm of chromosome 3 by somatic cell hybrid analysis. Annals of human genetics 6 9365790
2023 A novel variant of TNNC1 associated with severe dilated cardiomyopathy causing infant mortality and stillbirth: a case of germline mosaicism. Journal of genetics 3 36814108
2024 Investigating TNNC1 gene inheritance and clinical outcomes through a comprehensive familial study. American journal of medical genetics. Part A 1 39248034
2016 [Analysis of cardiac troponin C gene TNNC1 c. G175C mutation in a Chinese pedigree with familial hypertrophic cardiomyopathy and the correlation between genotype and phenotype]. Zhonghua xin xue guan bing za zhi 0 28056232

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