Affinage

TPM1

Tropomyosin alpha-1 chain · UniProt P09493

Length
284 aa
Mass
32.7 kDa
Annotated
2026-06-10
84 papers in source corpus 41 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TPM1 encodes tropomyosin, a coiled-coil protein that binds F-actin filaments head-to-tail to stabilize them and regulate actin-based processes from vesicle transport to muscle contraction (PMID:1629236, PMID:41067737). In yeast, Tpm1p is required to maintain actin cables and directed myosin (MYO2)-dependent secretory vesicle delivery to the cell surface, a function it performs non-redundantly with a second tropomyosin (PMID:1629236, PMID:7844152); full F-actin binding activity depends on N-terminal acetylation by the NatB complex, which requires Mdm20p acting cooperatively with the catalytic subunit Nat3p (PMID:12808144, PMID:11014803). In striated muscle, tropomyosin positions on the thin filament to gate Ca2+-dependent actin-myosin crossbridge cycling, and a large series of human cardiomyopathy mutations perturb this regulation through distinct molecular routes: HCM mutations shift tropomyosin toward the open/closed activating states and increase Ca2+ sensitivity and strong-binding crossbridges, whereas DCM mutations reduce the proportion of strong-binding states or alter troponin-tropomyosin allostery to produce hyposensitivity (PMID:21376702, PMID:22155441, PMID:25548289, PMID:39436707, PMID:21741356). Mechanistic studies combining molecular dynamics, in vitro motility, and patient-derived engineered heart tissues show that changes in tropomyosin flexibility and tropomyosin-actin contacts drive hypercontractility or depressed contractility, and that myosin modulators such as mavacamten can reverse these contractile phenotypes (PMID:34319370, PMID:36896133, PMID:39282088, PMID:39436707). Alternative splicing of TPM1 exons (controlled by MBNL1/PTB and SRPK3) generates structurally and functionally distinct cytoplasmic and striated isoforms that differ in actin affinity, filament stiffness, end-to-end interactions, and subcellular targeting (PMID:23511971, PMID:34067970, PMID:38999987, PMID:42261667). Non-muscle TPM1 isoforms protect actin filaments from cofilin-mediated severing, localize to the lamellipodium, and stabilize the endothelial cytoskeleton and cell-cell junctions to restrain inflammatory signaling (PMID:41067737, PMID:41085091, PMID:34604206). TPM1 expression is also repressed post-transcriptionally by miR-21 and by m6A-dependent mRNA decay (RBM15, FTO), and transcriptionally silenced by EZH2/lncRNA and ELF3, with re-expression suppressing tumor growth in several cancer contexts (PMID:17363372, PMID:37854295, PMID:42215832, PMID:33499872, PMID:40611880). A dominant TPM1 mutation causing atrial septal defect and embryonic-lethal myofibril disassembly is genetically suppressed by a TLN2 variant, directly linking TPM1 to a Mendelian cardiac structural disease (PMID:35243414).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1992 High

    Established that tropomyosin is functionally required to maintain actin cables and support polarized secretory vesicle transport, defining its core cytoskeletal role beyond passive filament binding.

    Evidence Yeast TPM1 gene disruption with secretory-pathway epistasis (sec mutants) and synthetic lethality with myo2

    PMID:1629236

    Open questions at the time
    • Does not address mammalian striated-muscle function
    • Mechanism of myosin-tropomyosin coordination on cables not resolved
  2. 1995 High

    Showed that distinct tropomyosins occupy different filament periodicities and are non-redundant, establishing that tropomyosin isoform identity, not just presence, determines function.

    Evidence Protein purification, F-actin competition assays, and double-mutant lethality in yeast

    PMID:7844152

    Open questions at the time
    • Molecular basis of the spacing difference (4 vs 5 monomers) not structurally defined
    • Relevance to mammalian isoforms untested here
  3. 2003 High

    Identified an upstream post-translational requirement for tropomyosin activity, showing N-terminal acetylation by NatB licenses F-actin binding.

    Evidence N-terminal acetylation assay, acetylated vs unacetylated F-actin binding comparison, mdm20/nat3 epistasis in yeast (building on 2000 suppressor screen)

    PMID:11014803 PMID:12808144

    Open questions at the time
    • Whether mammalian TPM1 isoforms have the same acetylation dependence not shown
    • Structural basis of acetylation-enhanced binding not resolved
  4. 2008 Medium

    Defined cis- and trans-acting control of a TPM1 splicing decision, opening the mechanism by which isoform diversity is generated.

    Evidence Mutagenesis of cis-elements and splicing reporter assays in rat Tpm1, with hnRNP H/F and MBNL/PTB

    PMID:19037011

    Open questions at the time
    • Functional consequence of the regulated isoform not addressed
    • Single-lab reporter system
  5. 2013 High

    Established MBNL1 as an allosteric repressor that cooperates with PTB to control Tpm1 exon inclusion, explaining combinatorial splicing regulation.

    Evidence RNA binding, protein-protein interaction, single-molecule and domain-deletion analyses with splicing reporters

    PMID:23511971

    Open questions at the time
    • In vivo physiological output of this exon choice not quantified
    • Tissue-specificity of the MBNL/PTB complex not mapped
  6. 2007 High

    Identified TPM1 as a translationally repressed miR-21 target and a tumor-suppressive cytoskeletal regulator, linking its downregulation to transformed phenotypes.

    Evidence 3'-UTR luciferase reporter with binding-site deletion, Western blot, anchorage-independent growth assay in breast cancer cells

    PMID:17363372

    Open questions at the time
    • Which TPM1 isoforms mediate growth suppression not resolved
    • Downstream actin-dependent tumor-suppressive mechanism not defined here
  7. 2014 High

    Demonstrated that HCM and DCM mutations diverge in their direction of effect on Ca2+ sensitivity, providing a unifying biochemical framework distinguishing the two disease classes.

    Evidence Ca2+-dependent β-cardiac myosin ATPase, TnC conformational probes, stability and interaction assays on seven mutants

    PMID:21376702 PMID:21741356 PMID:22155441 PMID:25548289 PMID:27480605

    Open questions at the time
    • Did not connect biochemistry to whole-tissue contractile output
    • Structural states inferred indirectly
  8. 2018 Medium

    Quantified tropomyosin assembly kinetics on single actin filaments, grounding regulatory models in measured nucleation, elongation, and dissociation rates.

    Evidence Single-molecule TIRF microscopy with microfluidics and kymograph analysis

    PMID:30532204

    Open questions at the time
    • Performed on skeletal Tpm1.1 only
    • Methodology paper, limited isoform comparison
  9. 2024 High

    Connected molecular-scale tropomyosin defects to tissue-level contractile dysfunction and pharmacological rescue, validating excess/deficient crossbridge activity as the pathogenic axis.

    Evidence Molecular dynamics, Markov thin-filament models, in vitro motility, iPSC-derived engineered heart tissues, and myosin modulator/mavacamten rescue across multiple mutations (E192K, S215L, E62Q, E54K, M8R, K30E)

    PMID:34319370 PMID:36896133 PMID:39282088 PMID:39436707 PMID:39684770

    Open questions at the time
    • Long-term in vivo effects of modulators not addressed
    • Genotype-specific clinical thresholds not defined
  10. 2022 High

    Provided direct Mendelian evidence that TPM1 is required for myofibril assembly and cardiac morphogenesis, with a genetic modifier explaining variable lethality.

    Evidence Five-generation pedigree exome sequencing, CRISPR knock-in mouse rescue with TLN2, and iPSC-derived cardiomyocytes

    PMID:35243414

    Open questions at the time
    • Molecular basis of TLN2 suppression of TPM1 not resolved
    • Mechanism linking myofibril disassembly to ASD not defined
  11. 2025 Medium

    Defined functionally distinct cytoplasmic TPM1 isoforms that protect actin from cofilin severing and localize to specific cytoskeletal compartments, establishing isoform-specific non-muscle roles.

    Evidence Recombinant isoform biochemistry (co-sedimentation, optical-trap stiffness, cofilin protection) and isoform-specific lamellipodial localization with pharmacological perturbation

    PMID:34067970 PMID:38999987 PMID:41067737 PMID:41085091

    Open questions at the time
    • In vivo contribution of each isoform to cell migration not quantified
    • Single-lab biochemical systems
  12. 2022 Medium

    Revealed non-canonical signaling and extracellular roles for TPM1 in inflammation, vascular remodeling, platelet function, and intercellular vesicle transfer, broadening its biology beyond intracellular actin regulation.

    Evidence TPM1 knockdown/KO and overexpression with RNA-seq, parabiosis, EV transfer, CRISPRa, and conditional KO across retinal, endothelial, smooth-muscle, platelet, and cardiac systems (TREM2/PKA/CREB, LGALS9/CD45, P53/SHISA5, TSPAN4)

    PMID:33661765 PMID:34604206 PMID:35148456 PMID:36241997 PMID:40221727 PMID:41004162 PMID:42202020

    Open questions at the time
    • How an actin-binding protein acts as a circulating/secreted signaling factor mechanistically unclear
    • Most findings single-lab and context-specific
    • Direct receptor engagement not demonstrated
  13. 2026 Medium

    Established multilayered post-transcriptional and transcriptional control of TPM1 abundance (m6A, lncRNA/EZH2, ELF3, circRNA-driven splicing) tying its repression to cancer progression.

    Evidence MeRIP/RIP, RNA pulldown-MS, ChIP, and rescue assays linking RBM15, FTO, EZH2/LINC01116, ELF3, and CircNSD2/SRSF6 to TPM1 in colorectal, AML, endometrial, and breast cancers

    PMID:33499872 PMID:37854295 PMID:40515937 PMID:40611880 PMID:41808072 PMID:42215832

    Open questions at the time
    • Whether downstream tumor effects require TPM1's actin function not resolved
    • Isoform identity of regulated transcripts often unspecified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How tropomyosin's biophysical filament-stabilizing activity is mechanistically unified with its emerging roles as a secreted/EV-transferred signaling factor and immune regulator remains unresolved.
  • No structural model linking specific isoforms to specific signaling outputs
  • Receptor and trafficking mechanisms for extracellular TPM1 undefined
  • Integration of cardiomyopathy biophysics with cytoplasmic isoform diversity in vivo unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 6 GO:0098772 molecular function regulator activity 4 GO:0005198 structural molecule activity 3
Localization
GO:0005856 cytoskeleton 4 GO:0005829 cytosol 3 GO:0005886 plasma membrane 2
Pathway
R-HSA-8953854 Metabolism of RNA 5 R-HSA-1643685 Disease 4 R-HSA-397014 Muscle contraction 4 R-HSA-168256 Immune System 3 R-HSA-9609507 Protein localization 1
Partners
ACT1MBNL1MYO2PTBTLN2TSPAN4YAP1

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 Disruption of yeast TPM1 causes loss of actin cables, accumulation of secretory vesicles, and defects in directed vesicular transport to the cell surface. Genetic interaction with MYO2 (myosin-like protein) shows synthetic lethality, placing TPM1/actin cables in the same pathway as MYO2-dependent vesicle delivery. Combinations with sec1, sec4, or sec6 mutations did not affect vesicle accumulation, while sec13 or sec18 combinations blocked it, positioning TPM1 function downstream of early secretory pathway steps. Genetic disruption, secretory pathway epistasis with sec mutants, synthetic lethality with myo2-66, secretion timing assays, electron microscopy of vesicle accumulation The Journal of cell biology High 1629236
1995 Yeast Tpm2p spans four actin monomers along a filament whereas Tpm1p spans five. Tpm2p can compete with Tpm1p for F-actin binding. Loss of Tpm2p is lethal in combination with tpm1Δ, demonstrating that the two tropomyosins perform an essential but non-redundant function. Over-expression of Tpm2p does not suppress the growth or cell surface targeting defects of tpm1Δ, indicating the two tropomyosins are not functionally interchangeable. Protein purification and biochemical characterization, F-actin competition assays, genetic double-mutant lethality, overexpression complementation assays The Journal of cell biology High 7844152
2000 Suppressor mutations in TPM1 (and ACT1) rescue temperature-sensitive growth, mitochondrial inheritance defects, and actin cable loss caused by mdm20 deletion. The ACT1 suppressor mutations cluster in the region predicted to contact tropomyosin, suggesting these alleles stabilize actin cables by enhancing actin-tropomyosin interactions. Second-site suppressor screen, genetic analysis of haploid and diploid mdm20 strains, actin cable visualization Genetics Medium 11014803
2003 Mdm20p is required for N-terminal acetylation of Tpm1p by the NatB acetyltransferase complex (catalytic subunit Nat3p). Unacetylated Tpm1p has severely reduced F-actin binding activity compared to acetylated Tpm1p, and genetic evidence shows Mdm20p functions cooperatively with Nat3p to enable Tpm1p association with and stabilization of actin filaments and cables. N-terminal acetylation assay, F-actin binding activity comparison of acetylated vs. unacetylated Tpm1p, genetic epistasis between mdm20 and nat3 mutants Proceedings of the National Academy of Sciences of the United States of America High 12808144
2007 miR-21 directly targets the 3'-UTR of TPM1 variants V1 and V5 to repress TPM1 protein expression at the translational level (no change in mRNA). Deletion of the miR-21 binding site in the 3'-UTR abolishes this repression. Overexpression of TPM1 in MCF-7 breast cancer cells suppresses anchorage-independent growth. 2D-DIGE proteomics, luciferase 3'-UTR reporter assay with binding site deletion, Western blot, RT-qPCR, anchorage-independent growth assay The Journal of biological chemistry High 17363372
2008 A nonsense exon in the rat Tpm1 gene is silenced by hnRNP H and F binding to a G-rich silencer element at its 5' end. RNA binding by MBNL promotes a conformational change that facilitates MBNL interaction with PTB. Computational predictions of splicing enhancer/silencer elements in this exon were confirmed experimentally (11 of 13 tested mutations behaved as predicted). Mutagenesis of cis-acting elements, splicing reporter assays, binding predictions validated by mutational analysis RNA (New York, N.Y.) Medium 19037011
2011 The dilated cardiomyopathy-causing Glu40Lys mutation in α-tropomyosin (TPM1) inhibits movement of actin subdomain-1 and the SH1 helix of myosin S1 during the ATPase cycle, specifically at the transition from AM**·ADP·Pi to AM state, decreasing the proportion of strong-binding actomyosin sub-states. This structural change underlies the contractile deficit in DCM. Reconstituted ghost muscle fiber system with fluorescently labeled actin (Cys374) and myosin S1 (Cys707), polarized fluorimetry during ATPase cycle Biochemical and biophysical research communications Medium 21741356
2011 HCM-causing Asp175Asn and Glu180Gly mutations in α-tropomyosin (TPM1) shift tropomyosin strands towards the open position on the thin filament during the ATPase cycle and increase the proportion of strong-binding cross-bridge sub-states, with Glu180Gly having a greater effect than Asp175Asn. This increased Ca2+ sensitivity provides a structural basis for altered cardiac muscle contraction. Fluorescently labeled recombinant tropomyosins incorporated into ghost muscle fibers, polarized fluorimetry during ATPase cycle stages Biochemical and biophysical research communications Medium 21376702 22155441
2013 MBNL1 (via its N-terminal CCCH zinc-finger domains) acts as a repressor of Tpm1 exon 3 splicing by binding UGC/CUG clusters. MBNL1 makes a direct protein-protein interaction with PTB, and RNA binding by MBNL promotes this interaction via a conformational change. MBNL binding sites also increase PTB binding to its own sites, suggesting allosteric assembly of a cooperative RNA-protein repressor complex. RNA binding assays, protein-protein interaction assays, single molecule analysis of PTB binding, domain deletion mutagenesis of MBNL1, splicing reporter assays Nucleic acids research High 23511971
2014 Seven HCM/DCM-associated TPM1 mutants (E62Q, D84N, I172T, L185R, S215L, D230N, M281T) show distinct effects on Ca2+ sensitivity of human β-cardiac myosin ATPase activity: HCM mutants are hypersensitive and DCM mutants are hyposensitive to Ca2+ activation. Mutants also show changes in TnC conformational changes (measured by fluorescent probe), protein stability, and protein-protein interactions, indicating multiple mechanistic pathways. Ca2+ sensitivity of human β-cardiac myosin ATPase activity measurements, fluorescent probe monitoring of TnC conformational changes, protein stability assays, protein-protein interaction assays The Journal of biological chemistry High 25548289
2016 Arg167His, Arg167Gly, and Lys168Glu substitutions in the consensus actin-binding site of Tpm1.1 alter azimuthal movement of tropomyosin on actin during the ATPase cycle. Arg167Gly and Lys168Glu shift TM strands toward the filament center and abnormally increase strongly-bound myosin heads even under relaxation conditions, while Arg167His shifts TM toward the periphery and reduces strongly-bound myosin heads throughout the ATPase cycle. These altered TM-actin contacts destabilize the thin filament. Fluorescence polarization of ghost muscle fibers containing labeled recombinant TM, labeled myosin S1, and FITC-phalloidin F-actin; polarized fluorimetry at defined ATPase cycle stages Archives of biochemistry and biophysics Medium 27480605
2018 Skeletal muscle tropomyosin Tpm1.1 associates with and dissociates from single actin filaments with measurable nucleation, elongation, and dissociation rates. Tpm1.1 interactions can be resolved on both sides of individual actin filaments by single-molecule TIRF microscopy. Single molecule fluorescence TIRF microscopy with microfluidic device, fluorescently labeled Tpm1.1 on single actin filaments, kymograph analysis PloS one Medium 30532204
2019 TPM1 mutations cause dysfunction in thin filament regulation including altered Ca2+-dependent control of actin-myosin interactions, perturbation of tropomodulin and leiomodin binding at the thin filament pointed end, and changes in thin filament length. Specific mutations in Tpm1.1 affect distinct binding partner interactions along the coiled-coil. Review integrating functional mutation studies; mechanistic findings derive from cited experimental work on actin-myosin ATPase, pointed end regulation assays Journal of muscle research and cell motility Low 31270709
2021 TPM1 E192K mutation increases molecular flexibility of the tropomyosin molecule (molecular dynamics), reduces Ca2+ sensitivity in in vitro motility assays of regulated actin filaments, and causes loss of complete inhibition of actin-myosin crossbridge activity at low Ca2+. Patient-derived engineered heart tissues show cellular hypertrophy, hypercontractility, and diastolic dysfunction. Chronic treatment with the cardiac myosin inhibitor mavacamten abolished contractile differences and reversed cardiomyocyte hypertrophy, confirming excess residual crossbridge activity as the pathogenic mechanism. Molecular dynamics simulation, in vitro motility assay, multiscale computational modeling, patient-derived iPSC-engineered heart tissues, mavacamten pharmacological rescue The Journal of general physiology High 34319370
2021 LINC01116 recruits EZH2 to the TPM1 promoter, resulting in H3K27me3-mediated transcriptional silencing of TPM1, thereby promoting colorectal cancer cell proliferation and angiogenesis. RNA pull-down, RIP assay, ChIP assay for EZH2 and H3K27me3 at TPM1 promoter, xenograft model Journal of translational medicine Medium 33499872
2021 ORMDL3 expression selectively in airway smooth muscle induces increased TPM1 and TPM4 protein levels. siRNA knockdown of TPM1 demonstrates its requirement for ORMDL3-mediated ASM hyperplasia (proliferation) but not hypertrophy. Transgenic mouse (Cre-loxP), siRNA knockdown of TPM1, BrdU incorporation for proliferation, FACS and image analysis for hypertrophy JCI insight Medium 33661765
2021 CRISPR-based activation of endogenous TPM1 expression stabilizes the actin cytoskeleton in TNFα-stimulated human coronary artery endothelial cells, inhibiting inflammatory response, reducing VE-cadherin cleavage, and maintaining stable levels of α- and β-catenins at cell-cell junctions. TPM1 activation also reduced inflammatory activation, proliferation, and migration of primary human coronary artery smooth muscle cells. CRISPRa transcriptional activation of endogenous TPM1, immunofluorescence of F-actin and junctional proteins, Western blot for VE-cadherin/catenins, migration assays Frontiers in cell and developmental biology Medium 34604206
2022 TPM1 drives LPS-induced neuroinflammation and neuronal death in the retina via the PKA/CREB signaling pathway. TPM1 acts downstream of TREM2: TPM1 knockdown in WT retinas reduces inflammation via CREB-mediated anti-inflammatory gene expression, but exaggerates inflammation in TREM2-/- retinas, where CREB instead drives pro-inflammatory genes. TREM2 thus acts as a brake on TPM1-mediated inflammation. TPM1 siRNA knockdown in WT and TREM2-/- retinas, RNA sequencing, immunocytochemistry, Western blot, qPCR, TUNEL, electroretinogram, CX3CR1CreER:Rosa26iDTR microglia depletion model Journal of neuroinflammation Medium 36241997
2022 Systemic TPM1 protein promotes retinal inflammation and ectopic dendritic sprouting of rod bipolar and horizontal cells in aging retinas by phosphorylating PKA and regulating the FABP5/NF-κB signaling pathway. Heterochronic parabiosis and plasma transfer experiments confirmed TPM1 as a circulating pro-aging factor; anti-TPM1 neutralizing antibody treatment ameliorated age-related structural and functional changes, and TPM1-depleted old plasma failed to induce aging effects in young mice. Heterochronic parabiosis, plasma transfer, recombinant TPM1 protein administration, anti-TPM1 neutralizing antibody treatment, proteomic analysis, Western blot, PKA phosphorylation assays Aging cell Medium 35148456
2022 The AZGP1P2 pseudogene binds UBA1 (E1 ubiquitin-activating enzyme) and RBM15 (m6A writer). UBA1 promotes RBM15 protein degradation via ubiquitination. RBM15 controls TPM1 mRNA decay via m6A methylation, such that when AZGP1P2 is present, RBM15 is degraded, reducing m6A-mediated TPM1 mRNA decay and increasing TPM1 expression. RNA pull-down with mass spectrometry, co-immunoprecipitation, RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation (MeRIP), xenograft mouse model, patient-derived organoids Research (Washington, D.C.) Medium 37854295
2023 TPM1 S215L destabilizes the blocked regulatory state of tropomyosin on actin (molecular dynamics) and increases flexibility. In vitro motility with TPM1 S215L thin filaments shows higher Ca2+ sensitivity than wild type. 3D engineered heart tissues expressing S215L exhibit hypercontractility, diastolic dysfunction, and hypertrophic gene upregulation. Computational modeling starting from molecular stiffness changes reproduced observed contractile phenotypes. Molecular dynamics simulation, Markov model of thin filament activation, in vitro motility assay, 3D genetically engineered heart tissues (iPSC-derived cardiomyocytes) PNAS nexus High 36896133
2023 Diacetylmorphine (heroin) causes increased autophosphorylation of CaMKII (at Thr287) in myocardium and concomitant dysregulation of the myocardial contractile protein TPM1. CaMKII inhibitor KN-93 rescues toxic effects on cardiomyocytes and abnormal ECG changes, indicating TPM1 regulation by CaMKII is downstream of opioid-induced CaMKII activation. TMT quantitative proteomics, Western blot for CaMKII phosphorylation (Thr287), KN-93 pharmacological inhibition in vitro and in vivo (rat ECG) Scientific reports Medium 37037889
2024 TPM1 E62Q (HCM) acts via reduced effective molecular stiffness and alterations in tropomyosin-actin interactions that favor the closed regulatory state, producing increased Ca2+ sensitivity and hypercontractility. TPM1 E54K (DCM) acts via long-range allosteric interactions that increase the association rate of the C-terminal troponin I mobile domain to tropomyosin/actin, producing hyposensitivity. These distinct molecular mechanisms produce diverging gene expression in human engineered heart tissues, and myosin modulators (activator and inhibitor) rescue normal contractility in accordance with predictions. Computational thin-filament simulations, iPSC-derived cardiomyocytes engineered heart tissues, myosin modulator pharmacological rescue, gene expression analysis The Journal of clinical investigation High 39436707
2024 TPM1 Lys30Glu (K30E) de novo mutation decreases thermal stability of tropomyosin and its complex with actin, significantly reduces sliding velocity of regulated thin filaments over cardiac myosin across the entire physiological Ca2+ concentration range (in vitro motility assay), and molecular dynamics simulations suggest K30E alters the actin monomer to which tropomyosin is bound, hindering myosin head transition to a strongly-bound force-generating state. Recombinant protein production, biochemical stability assays, in vitro motility assay, molecular dynamics simulation International journal of molecular sciences Medium 39684770
2024 TPM1 M8R increases flexibility of the tropomyosin chain and enhances affinity for the blocked/inactive state on actin (atomistic simulations). Markov model incorporating these molecular effects reproduced shifts in Ca2+ sensitivity, maximum force reduction, and cooperativity drop observed in vitro. Human engineered heart tissues expressing M8R via adenovirus showed depressed contractility and reduced twitch duration agreeing with model predictions. Tropomyosin-actin interaction changes contribute more than chain stiffness to cardiac twitch dysfunction. Atomistic molecular dynamics simulation, Markov thin-filament model, in vitro motility assay, adenoviral expression in human engineered heart tissues, isometric twitch force measurement Frontiers in physiology High 39282088
2021 Non-muscle TPM1-encoded isoforms (Tpm1.5, Tpm1.6, Tpm1.7, Tpm1.12, Tpm4.2) differ in structural and functional properties depending on alternatively spliced exon composition, particularly the N-terminal (1a2b or 1b), internal (6a or 6b), and C-terminal exons. These differences affect their interactions with actin filaments. Biochemical characterization of recombinant isoforms (thermal stability, F-actin binding, actin filament stiffness via optical trap) International journal of molecular sciences Medium 34067970
2022 Genetic analysis in a five-generation pedigree reveals a dominant lethal TPM1 mutation (causing ASD in surviving patients) is suppressed by a variant in TLN2 (another myofilament actin-binding protein). CRISPR knock-in mice carrying both TPM1 and TLN2 variants rescue embryonic lethality with near-term fetuses exhibiting large ASD, while TPM1 mutation alone causes early embryonic lethality with disrupted myofibril assembly. Patient iPSC-derived cardiomyocytes show normal beating with mild myofilament defect. Whole exome sequencing, CRISPR knock-in mouse models, iPSC-derived cardiomyocyte functional assays, genetic suppressor analysis Cell reports. Medicine High 35243414
2025 TSPAN4 interacts with and influences the expression and localization of TPM1 in vascular smooth muscle cells (VSMCs). TSPAN4 overexpression promotes phenotypic switching from contractile to synthetic state with enhanced proliferation and migration; TSPAN4 knockdown suppresses PDGF-BB-induced switching. This is mechanistically mediated through TPM1, affecting cytoskeletal organization. TSPAN4 deficiency in mice attenuates neointimal formation after carotid artery ligation. Immunoprecipitation (TSPAN4-TPM1 interaction), Western blot, EdU proliferation assay, Transwell migration assay, carotid artery ligation in TSPAN4-deficient mice Clinical science (London, England : 1979) Medium 41004162
2025 High lipid stimulation increases TPM1 expression in cardiomyocytes; TPM1 protein is transferred to cardiac fibroblasts via extracellular vesicles and activates the P53/SHISA5 signaling axis, inducing ER stress and autophagy, thereby promoting atrial structural remodeling and fibrosis. Extracellular vesicle isolation and characterization, Western blot, immunohistochemistry, immunofluorescence, transmission electron microscopy for autophagy, proteomic and transcriptomic sequencing Lipids in health and disease Medium 40221727
2026 SRPK3 mediates alternative splicing of TPM1 exon 9a. In HFpEF, upregulation of SRPK3 promotes skipping of exon 9a, producing the TPM1b isoform. Cardiomyocyte-specific overexpression of TPM1b (without exon 9a) exacerbates HFpEF phenotypes; supplementation with exon 9a-containing TPM1 partially rescues diastolic dysfunction caused by SRPK3 overexpression. SRPK3 knockdown ameliorates myofiber disarray and diastolic dysfunction in HFpEF mouse model. RNA pulldown, mass spectrometry, alternative splicing analysis, adeno-associated virus (AAV9) cardiomyocyte-specific overexpression/knockdown in mice, human pluripotent stem cell-derived cardiomyocytes, transmission electron microscopy, nanoindentation of myocardial compliance Circulation High 42261667
2026 TPM1-p.E181K mutation suppresses intracellular Ca2+ transients and inhibits CaMKII/HDAC4 phosphorylation in cardiomyocytes, resulting in impaired troponin activity and abnormal contractility. The mutation does not alter overall TPM1 protein expression or mitochondrial activity, indicating a gain-of-function effect on Ca2+-CaMKII-HDAC4 signaling. 3D protein modeling, AC16 cardiomyocyte transfection, Rhod-2 AM calcium imaging, Phalloidin-488 F-actin staining, Western blot for CaMKII/HDAC4 phosphorylation, qPCR Frontiers in genetics Medium 41568329
2026 TPM1 acts as a cytoskeletal-immune regulator in retinal microglia. Genetic ablation of Tpm1 attenuates microglial reactivity and preserves vision in rd10 mice. TPM1 overexpression triggers self-reinforcing neuroinflammation via: (i) AP-1 hyperactivation and SASP through MAPK/ERK3 signaling; (ii) SASP-mediated reduced phagocytosis; (iii) Tpm1-Apoe/Fabp5 axis disruption causing lipid droplet accumulation; (iv) LGALS9/CD45-mediated intermicroglial inflammatory propagation. Multiomics profiling of rd10 mice, Tpm1 genetic ablation and overexpression, immunofluorescence, Western blot, phagocytosis assays, lipid droplet analysis Science advances Medium 42202020
2025 Tpm1 knockout in platelets (via Vav-Cre) increases platelet lifespan, diminishes platelet adhesion to fibronectin and fibrinogen, reduces clot contraction, and enhances clot formation/vascular occlusion in a ferric chloride-induced stroke model. Endothelial Tpm1 deletion (Cdh5-Cre) increases hemogenic endothelial cell specification but does not change adult blood counts. These results establish separate roles for Tpm1 in platelet function vs. hematopoiesis. Conditional knockout mice (Cdh5-Cre and Vav-Cre), platelet lifespan assays, platelet adhesion assays (fibronectin, fibrinogen), clot contraction assay, ferric chloride-induced stroke model bioRxivpreprint Medium bio_10.1101_2025.07.31.667883
2024 Cytoplasmic TPM1 isoforms Tpm1.8 and Tpm1.9 differ in the strength of end-to-end interactions and affinity for F-actin, determined by whether alternative internal exon 6a or 6b is included. Both isoforms form rigid actin filaments (stiffness measured by optical trap) and strongly interact with F-actin. Recombinant protein biochemical characterization, co-sedimentation assays, optical trap stiffness measurement, thermal stability assays International journal of molecular sciences Medium 38999987
2025 TPM1-encoded isoforms Tpm1.7, Tpm1.8, and Tpm1.9 significantly inhibit cofilin-1 (cof-1) binding to F-actin surface (co-sedimentation assays). Tpm1.1, Tpm1.8, and Tpm1.6 effectively prevented depolymerizing/severing action of cof-1 on actin filaments; protective effect of Tpm1.7 and Tpm1.9 was less pronounced. All tested TPM1 isoforms prevented cof-1-induced conformational changes in F-actin (rhodamine-phalloidin displacement assay). Co-sedimentation assay, viscometry for actin depolymerization/severing, rhodamine-phalloidin displacement assay Biochemistry. Biokhimiia Medium 41067737
2025 TPM1 overexpression in NSCLC cells inhibits proliferation, migration, and invasion while promoting apoptosis. Co-immunoprecipitation established a direct interaction between TPM1 and YAP1, and TPM1 overexpression downregulates YAP1 expression. YAP1 overexpression partially counteracts the anti-tumor effects of TPM1, placing TPM1 upstream of YAP1 in NSCLC suppression. Co-IP assay (TPM1-YAP1), Western blot, RT-qPCR, CCK-8, flow cytometry, scratch healing, Transwell assay Discover oncology Medium 40515937
2025 TPM1 isoforms Tpm1.8/1.9 are enriched in the lamellipodium of migrating cells. Small molecule compounds 189-3 and 189-1 target Tpm1.8/1.9 specifically and disperse them from lamellipodia without affecting Tpm3.1/3.2 association with stress fibers; 189-1 also targets Tpm4.2. The isoform specificity is determined by amino acid sequence differences in the first 19 residues. Tpm1.8/1.9 reorganization is reversible within 4 h of drug washout. Immunofluorescence localization in human fibroblasts and SK-N-SH cells, pharmacological compound treatment and washout, isoform-specific localization assays Cytoskeleton (Hoboken, N.J.) Medium 41085091
2026 FTO (m6A eraser) destabilizes TPM1 mRNA in an m6A-dependent manner in AML cells, reducing TPM1 expression. FTO depletion increases TPM1, and TPM1 downregulation reverses the effects of FTO depletion on AML cell proliferation, Ara-C sensitivity, and M2 macrophage polarization. MeRIP (methylated RNA immunoprecipitation), RIP, mRNA stability assay, siRNA knockdown, xenograft model, co-culture macrophage polarization assay Cell biology and toxicology Medium 42215832
2026 CircNSD2 acts as a scaffold to enhance interaction between SRSF6 and USP10, preventing K48-linked polyubiquitination of SRSF6 at lysine 16 and inhibiting its proteasomal degradation. Stabilized SRSF6 reprograms TPM1 alternative splicing, promoting TNBC metastasis. RNA pulldown, proteomic analysis, RNA immunoprecipitation, alternative splicing analysis, gain- and loss-of-function assays, ChIP, luciferase assay Molecular cancer Medium 41808072
2025 ELF3 transcription factor inhibits TPM1 transcription by binding to the TPM1 promoter region, thereby suppressing TPM1 expression and promoting EMT, proliferation, and migration in endometrial cancer cells. ChIP assay (ELF3 binding to TPM1 promoter), Western blot, RT-qPCR, CCK-8, clone formation, immunohistochemistry, subcutaneous xenograft Cytotechnology Medium 40611880

Source papers

Stage 0 corpus · 84 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). The Journal of biological chemistry 880 17363372
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
1992 Characterization of TPM1 disrupted yeast cells indicates an involvement of tropomyosin in directed vesicular transport. The Journal of cell biology 145 1629236
1995 Tropomyosin is essential in yeast, yet the TPM1 and TPM2 products perform distinct functions. The Journal of cell biology 125 7844152
2003 Mdm20 protein functions with Nat3 protein to acetylate Tpm1 protein and regulate tropomyosin-actin interactions in budding yeast. Proceedings of the National Academy of Sciences of the United States of America 88 12808144
2009 [Mutations in sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in patients with hypertrophic cardiomyopathy]. Revista espanola de cardiologia 59 19150014
2018 Long non-coding RNA MEG3 suppresses the development of bladder urothelial carcinoma by regulating miR-96 and TPM1. Cancer biology & therapy 48 30461333
2023 AZGP1P2/UBA1/RBM15 Cascade Mediates the Fate Determinations of Prostate Cancer Stem Cells and Promotes Therapeutic Effect of Docetaxel in Castration-Resistant Prostate Cancer via TPM1 m6A Modification. Research (Washington, D.C.) 44 37854295
2003 Variable clinical manifestation of a novel missense mutation in the alpha-tropomyosin (TPM1) gene in familial hypertrophic cardiomyopathy. Journal of the American College of Cardiology 44 12651045
2017 Natural antisense transcript TPM1-AS regulates the alternative splicing of tropomyosin I through an interaction with RNA-binding motif protein 4. The international journal of biochemistry & cell biology 43 28754317
2014 Mechanistic heterogeneity in contractile properties of α-tropomyosin (TPM1) mutants associated with inherited cardiomyopathies. The Journal of biological chemistry 42 25548289
2021 LINC01116 facilitates colorectal cancer cell proliferation and angiogenesis through targeting EZH2-regulated TPM1. Journal of translational medicine 39 33499872
2019 miRNA‑183‑5p.1 promotes the migration and invasion of gastric cancer AGS cells by targeting TPM1. Oncology reports 38 31638242
2010 Identification of a novel TPM1 mutation in a family with left ventricular noncompaction and sudden death. Molecular genetics and metabolism 38 20965760
2021 Inhibition of cancer cell-derived exosomal microRNA-183 suppresses cell growth and metastasis in prostate cancer by upregulating TPM1. Cancer cell international 37 33653339
2020 The MicroRNA MiR-29c Alleviates Renal Fibrosis via TPM1-Mediated Suppression of the Wnt/β-Catenin Pathway. Frontiers in physiology 37 32346368
2013 MBNL1 and PTB cooperate to repress splicing of Tpm1 exon 3. Nucleic acids research 37 23511971
2009 Presence of activating KRAS mutations correlates significantly with expression of tumour suppressor genes DCN and TPM1 in colorectal cancer. BMC cancer 36 19678923
1999 Tpm1, a locus controlling IL-12 responsiveness, acts by a cell-autonomous mechanism. Journal of immunology (Baltimore, Md. : 1950) 34 9973388
2019 Thin filament dysfunctions caused by mutations in tropomyosin Tpm3.12 and Tpm1.1. Journal of muscle research and cell motility 33 31270709
2002 A novel TPM1 mutation in a family with hypertrophic cardiomyopathy and sudden cardiac death in childhood. The American journal of cardiology 33 12423715
2022 TPM1 mediates inflammation downstream of TREM2 via the PKA/CREB signaling pathway. Journal of neuroinflammation 30 36241997
2000 Suppressors of mdm20 in yeast identify new alleles of ACT1 and TPM1 predicted to enhance actin-tropomyosin interactions. Genetics 29 11014803
2021 Loss of crossbridge inhibition drives pathological cardiac hypertrophy in patients harboring the TPM1 E192K mutation. The Journal of general physiology 28 34319370
2020 Circ0001320 inhibits lung cancer cell growth and invasion by regulating TNFAIP1 and TPM1 expression through sponging miR-558. Human cell 27 33128699
2020 Inhibition of miR-96 enhances the sensitivity of colorectal cancer cells to oxaliplatin by targeting TPM1. Experimental and therapeutic medicine 25 32765688
2015 Coexistence of Digenic Mutations in Both Thin (TPM1) and Thick (MYH7) Filaments of Sarcomeric Genes Leads to Severe Hypertrophic Cardiomyopathy in a South Indian FHCM. DNA and cell biology 25 25607779
2022 Accumulation of systematic TPM1 mediates inflammation and neuronal remodeling by phosphorylating PKA and regulating the FABP5/NF-κB signaling pathway in the retina of aged mice. Aging cell 24 35148456
2021 CRISPR-Based Activation of Endogenous Expression of TPM1 Inhibits Inflammatory Response of Primary Human Coronary Artery Endothelial and Smooth Muscle Cells Induced by Recombinant Human Tumor Necrosis Factor α. Frontiers in cell and developmental biology 24 34604206
2012 Genetic and epigenetic alterations are involved in the regulation of TPM1 in cholangiocarcinoma. International journal of oncology 23 23254774
2016 Functional Assessment of Clubfoot Associated HOXA9, TPM1, and TPM2 Variants Suggests a Potential Gene Regulation Mechanism. Clinical orthopaedics and related research 22 27020427
2013 Somatic MYH7, MYBPC3, TPM1, TNNT2 and TNNI3 mutations in sporadic hypertrophic cardiomyopathy. Circulation journal : official journal of the Japanese Circulation Society 20 23782526
1995 Assignment of the human skeletal muscle alpha-tropomyosin gene (TPM1) to band 15q22 by fluorescence in situ hybridization. Cytogenetics and cell genetics 20 7835079
2015 Silencing of the TPM1 gene induces radioresistance of glioma U251 cells. Oncology reports 18 25873252
2021 Structural and Functional Peculiarities of Cytoplasmic Tropomyosin Isoforms, the Products of TPM1 and TPM4 Genes. International journal of molecular sciences 17 34067970
2022 MYC-Induced Upregulation of Lncrna ELFN1-AS1 Contributes to Tumor Growth in Colorectal Cancer via Epigenetically Silencing TPM1. Molecular cancer research : MCR 14 35857351
2021 ORMDL3 expression in ASM regulates hypertrophy, hyperplasia via TPM1 and TPM4, and contractility. JCI insight 14 33661765
2011 The effect of the Asp175Asn and Glu180Gly TPM1 mutations on actin-myosin interaction during the ATPase cycle. Biochimica et biophysica acta 14 22155441
2017 Hypoxia and hyperoxia differentially control proliferation of rat neural crest stem cells via distinct regulatory pathways of the HIF1α-CXCR4 and TP53-TPM1 proteins. Developmental dynamics : an official publication of the American Association of Anatomists 13 28002632
2017 Left ventricular non-compaction with Ebstein anomaly attributed to a TPM1 mutation. European journal of medical genetics 13 29024827
2008 A nonsense exon in the Tpm1 gene is silenced by hnRNP H and F. RNA (New York, N.Y.) 13 19037011
1993 Chromosomal localization and genomic cloning of the mouse alpha-tropomyosin gene Tpm-1. Genomics 12 8406508
2023 CaMKII regulates the proteins TPM1 and MYOM2 and promotes diacetylmorphine-induced abnormal cardiac rhythms. Scientific reports 11 37037889
2021 ARHGAP11A Promotes the Malignant Progression of Gastric Cancer by Regulating the Stability of Actin Filaments through TPM1. Journal of oncology 11 34912455
2021 Knockdown of LncRNA NEAT1 inhibits myofibroblast activity in oral submucous fibrosis through miR-760/TPM1 axis. Journal of dental sciences 11 35756787
2011 The effect of the dilated cardiomyopathy-causing Glu40Lys TPM1 mutation on actin-myosin interactions during the ATPase cycle. Biochemical and biophysical research communications 11 21741356
2022 Genetic resiliency associated with dominant lethal TPM1 mutation causing atrial septal defect with high heritability. Cell reports. Medicine 10 35243414
2023 Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TPM1 variant S215L. PNAS nexus 9 36896133
2020 A novel homozygous TPM1 mutation in familial pediatric hypertrophic cardiomyopathy and in silico screening of potential targeting drugs. European review for medical and pharmacological sciences 8 32744700
2016 TPM1 polymorphisms and nonsyndromic orofacial clefts susceptibility in a Chinese Han population. American journal of medical genetics. Part A 8 26792422
2024 Distinct mechanisms drive divergent phenotypes in hypertrophic and dilated cardiomyopathy-associated TPM1 variants. The Journal of clinical investigation 7 39436707
2021 Generation of a TPM1 homozygous knockout embryonic stem cell line by CRISPR/Cas9 editing. Stem cell research 6 34352617
2019 Association of single nucleotide polymorphisms in the 3'UTR region of TPM1 gene with dilated cardiomyopathy: A case-control study. Medicine 6 31689804
2018 Interactions of tropomyosin Tpm1.1 on a single actin filament: A method for extraction and processing of high resolution TIRF microscopy data. PloS one 6 30532204
2014 Expression of TPM1κ, a Novel Sarcomeric Isoform of the TPM1 Gene, in Mouse Heart and Skeletal Muscle. Molecular biology international 6 24876965
2023 Immunohistochemical Expression of CD90, CD133, and TPM1 in Relation to Gastric Cancer and H. pylori Association. Asian Pacific journal of cancer prevention : APJCP 5 37378943
2022 Identification of a novel missense mutation in the TPM1 gene via exome sequencing in a Chinese family with dilated cardiomyopathy: A case report and literature review. Medicine 5 35029218
2011 Hypertrophic cardiomyopathy-causing Asp175asn and Glu180gly Tpm1 mutations shift tropomyosin strands further towards the open position during the ATPase cycle. Biochemical and biophysical research communications 4 21376702
2024 Identification of a novel likely pathogenic TPM1 variant linked to hypertrophic cardiomyopathy in a family with sudden cardiac death. ESC heart failure 3 38874371
2024 Functional and Structural Properties of Cytoplasmic Tropomyosin Isoforms Tpm1.8 and Tpm1.9. International journal of molecular sciences 3 38999987
2022 Derivation of YCMi005-A, a human-induced pluripotent stem cell line, from a patient with dilated cardiomyopathy carrying missense variant in TPM1 (p. Glu192Lys). Stem cell research 3 35176663
2016 Abnormal movement of tropomyosin and response of myosin heads and actin during the ATPase cycle caused by the Arg167His, Arg167Gly and Lys168Glu mutations in TPM1 gene. Archives of biochemistry and biophysics 3 27480605
2024 Nanofiber-based delivery of evodiamine impedes malignant properties of intrahepatic cholangiocarcinoma cells by targeting HDAC4 and restoring TPM1 transcription. Human cell 2 39073525
2024 In silico and in vitro models reveal the molecular mechanisms of hypocontractility caused by TPM1 M8R. Frontiers in physiology 2 39282088
2021 Association Between TPM1 Gene Polymorphisms and Idiopathic Congenital Talipes Equinovarus Risk in a Chinese Population. Genetic testing and molecular biomarkers 2 33945307
2018 Considering the downregulation of Tpm1.6 and Tpm1.7 in squamous cell carcinoma of esophagus as a potent biomarker. Personalized medicine 2 30259780
2016 [Corrigendum] Genetic and epigenetic alterations are involved in the regulation of TPM1 in cholangiocarcinoma. International journal of oncology 2 27779677
2025 High-fat stimulation induces atrial structural remodeling via the TPM1/P53/SHISA5 Axis. Lipids in health and disease 1 40221727
2025 TSPAN4 controls vascular smooth muscle cell phenotypic switching and intimal hyperplasia by targeting TPM1-regulated cytoskeletal organization. Clinical science (London, England : 1979) 1 41004162
2025 Effect of Non-Muscle Tropomyosin Isoforms Encoded by the TPM1 Gene on Cofilin-1 Activity toward Actin Filaments. Biochemistry. Biokhimiia 1 41067737
2024 Novel Mutation Lys30Glu in the TPM1 Gene Leads to Pediatric Left Ventricular Non-Compaction and Dilated Cardiomyopathy via Impairment of Structural and Functional Properties of Cardiac Tropomyosin. International journal of molecular sciences 1 39684770
2022 Generation of a heterozygous TPM1-E192K knock-in human induced pluripotent stem cell line using CRISPR/Cas9 system. Stem cell research 1 35917600
2022 A Novel TPM1 Mutation Causes Familial Hypertrophic Cardiomyopathy in an Indian Family: Genetic and Clinical Correlation. Indian journal of clinical biochemistry : IJCB 1 38223010
2015 [TPM1 gene mutation is associated with dilated cardiomyopathy in Kazaks in Xinjiang]. Zhonghua xin xue guan bing za zhi 1 26420121
2026 TPM1-p.E181K mutation suppresses CaMKII/HDAC4 signaling pathway leading to pediatric restrictive cardiomyopathy. Frontiers in genetics 0 41568329
2026 CircNSD2 promotes metastasis and immune escape by increasing the USP10/SRSF6-mediated alternative splicing of TPM1 in TNBC. Molecular cancer 0 41808072
2026 TPM1 drives cytoskeleton-immunometabolism coupling and LGALS9/CD45-mediated neuroinflammatory propagation in retinitis pigmentosa. Science advances 0 42202020
2026 Integrative multi-omics, machine learning, and experimental validation reveal that TPM1 suppresses M2 macrophage polarization and enhances chemosensitivity in acute myeloid leukemia. Cell biology and toxicology 0 42215832
2026 Alternative Splicing of TPM1 Mediated by SRPK3 Drives Cardiac Diastolic Dysfunction in Heart Failure With Preserved Ejection Fraction. Circulation 0 42261667
2025 Amplified TPM1 suppresses non-small cell lung cancer cells proliferation and metastasis. Discover oncology 0 40515937
2025 ELF3 regulates epithelial-mesenchymal transition through TPM1 and promotes the development of endometrial cancer. Cytotechnology 0 40611880
2025 Isoform Specificity of a Compound Targeting Actin Filaments Containing Tropomyosin Tpm1.8/1.9. Cytoskeleton (Hoboken, N.J.) 0 41085091
2025 Role of microRNA-183 based theranostics through targeting TPM1 in bladder cancer. Discover oncology 0 41231336
2025 The Evolutionarily Conserved TPM1 Super-Enhancer Drives Skeletal Muscle Regeneration via Mechanotransduction Signaling. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41243274

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