{"gene":"TPM1","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":1992,"finding":"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.","method":"Genetic disruption, secretory pathway epistasis with sec mutants, synthetic lethality with myo2-66, secretion timing assays, electron microscopy of vesicle accumulation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genetic epistasis experiments, multiple secretory pathway mutant combinations, replicated phenotypic readouts","pmids":["1629236"],"is_preprint":false},{"year":1995,"finding":"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.","method":"Protein purification and biochemical characterization, F-actin competition assays, genetic double-mutant lethality, overexpression complementation assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro biochemical assays combined with multiple genetic analyses in one study","pmids":["7844152"],"is_preprint":false},{"year":2000,"finding":"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.","method":"Second-site suppressor screen, genetic analysis of haploid and diploid mdm20 strains, actin cable visualization","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — suppressor screen with multiple alleles and phenotypic rescue, single lab","pmids":["11014803"],"is_preprint":false},{"year":2003,"finding":"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.","method":"N-terminal acetylation assay, F-actin binding activity comparison of acetylated vs. unacetylated Tpm1p, genetic epistasis between mdm20 and nat3 mutants","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — biochemical acetylation assay, F-actin binding comparison, and genetic epistasis in one study; directly establishes writer (NatB/Nat3p via Mdm20p) and functional consequence","pmids":["12808144"],"is_preprint":false},{"year":2007,"finding":"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.","method":"2D-DIGE proteomics, luciferase 3'-UTR reporter assay with binding site deletion, Western blot, RT-qPCR, anchorage-independent growth assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (reporter assay with deletion mutation, Western blot, functional growth assay) in one study; widely replicated finding across subsequent papers","pmids":["17363372"],"is_preprint":false},{"year":2008,"finding":"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).","method":"Mutagenesis of cis-acting elements, splicing reporter assays, binding predictions validated by mutational analysis","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic mutagenesis with computational prediction validation, single lab","pmids":["19037011"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Reconstituted ghost muscle fiber system with fluorescently labeled actin (Cys374) and myosin S1 (Cys707), polarized fluorimetry during ATPase cycle","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution with fluorescence polarimetry, single lab, single paper","pmids":["21741356"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Fluorescently labeled recombinant tropomyosins incorporated into ghost muscle fibers, polarized fluorimetry during ATPase cycle stages","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with polarized fluorimetry; two mutations tested in same study providing orthogonal comparison","pmids":["21376702","22155441"],"is_preprint":false},{"year":2013,"finding":"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.","method":"RNA binding assays, protein-protein interaction assays, single molecule analysis of PTB binding, domain deletion mutagenesis of MBNL1, splicing reporter assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (binding assays, protein interaction, single molecule analysis, mutagenesis) establishing mechanism in one study","pmids":["23511971"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Ca2+ sensitivity of human β-cardiac myosin ATPase activity measurements, fluorescent probe monitoring of TnC conformational changes, protein stability assays, protein-protein interaction assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple biochemical assays on seven mutants in one study, with functional readout directly linked to cardiomyopathy mechanism","pmids":["25548289"],"is_preprint":false},{"year":2016,"finding":"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.","method":"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","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with three different mutants providing comparative mechanistic data, single lab","pmids":["27480605"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Single molecule fluorescence TIRF microscopy with microfluidic device, fluorescently labeled Tpm1.1 on single actin filaments, kymograph analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct in vitro single molecule assay establishing kinetic parameters; single lab, methodology paper","pmids":["30532204"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Review integrating functional mutation studies; mechanistic findings derive from cited experimental work on actin-myosin ATPase, pointed end regulation assays","journal":"Journal of muscle research and cell motility","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review paper integrating prior experimental data; no new primary experiments reported in this abstract","pmids":["31270709"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Molecular dynamics simulation, in vitro motility assay, multiscale computational modeling, patient-derived iPSC-engineered heart tissues, mavacamten pharmacological rescue","journal":"The Journal of general physiology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (MD, in vitro assay, patient-derived cardiac tissues, pharmacological rescue) in one study establishing mechanism","pmids":["34319370"],"is_preprint":false},{"year":2021,"finding":"LINC01116 recruits EZH2 to the TPM1 promoter, resulting in H3K27me3-mediated transcriptional silencing of TPM1, thereby promoting colorectal cancer cell proliferation and angiogenesis.","method":"RNA pull-down, RIP assay, ChIP assay for EZH2 and H3K27me3 at TPM1 promoter, xenograft model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and RIP assays establish EZH2 recruitment to TPM1 promoter, single lab with in vivo validation","pmids":["33499872"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Transgenic mouse (Cre-loxP), siRNA knockdown of TPM1, BrdU incorporation for proliferation, FACS and image analysis for hypertrophy","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic model with siRNA validation distinguishing proliferation vs. hypertrophy roles, single lab","pmids":["33661765"],"is_preprint":false},{"year":2021,"finding":"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.","method":"CRISPRa transcriptional activation of endogenous TPM1, immunofluorescence of F-actin and junctional proteins, Western blot for VE-cadherin/catenins, migration assays","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPRa with multiple cellular readouts; single lab, orthogonal assays","pmids":["34604206"],"is_preprint":false},{"year":2022,"finding":"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.","method":"TPM1 siRNA knockdown in WT and TREM2-/- retinas, RNA sequencing, immunocytochemistry, Western blot, qPCR, TUNEL, electroretinogram, CX3CR1CreER:Rosa26iDTR microglia depletion model","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO model with RNA-seq and multiple orthogonal readouts; pathway placement by epistasis; single lab","pmids":["36241997"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Heterochronic parabiosis, plasma transfer, recombinant TPM1 protein administration, anti-TPM1 neutralizing antibody treatment, proteomic analysis, Western blot, PKA phosphorylation assays","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vivo models (parabiosis, plasma, recombinant protein, neutralizing antibody) establishing systemic signaling role; single lab","pmids":["35148456"],"is_preprint":false},{"year":2022,"finding":"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.","method":"RNA pull-down with mass spectrometry, co-immunoprecipitation, RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation (MeRIP), xenograft mouse model, patient-derived organoids","journal":"Research (Washington, D.C.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods (pull-down MS, Co-IP, RIP, MeRIP) establishing the AZGP1P2/UBA1/RBM15/TPM1 axis; single lab","pmids":["37854295"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Molecular dynamics simulation, Markov model of thin filament activation, in vitro motility assay, 3D genetically engineered heart tissues (iPSC-derived cardiomyocytes)","journal":"PNAS nexus","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — integrated computational and experimental pipeline with in vitro motility and patient-relevant engineered tissue; orthogonal methods converging on same mechanism","pmids":["36896133"],"is_preprint":false},{"year":2023,"finding":"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.","method":"TMT quantitative proteomics, Western blot for CaMKII phosphorylation (Thr287), KN-93 pharmacological inhibition in vitro and in vivo (rat ECG)","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics combined with pharmacological rescue in vitro and in vivo; single lab","pmids":["37037889"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Computational thin-filament simulations, iPSC-derived cardiomyocytes engineered heart tissues, myosin modulator pharmacological rescue, gene expression analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — integrated computational and experimental approach with patient-derived cardiac tissues and pharmacological validation; two mutations with distinct mechanistic explanations confirmed orthogonally","pmids":["39436707"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Recombinant protein production, biochemical stability assays, in vitro motility assay, molecular dynamics simulation","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with motility assay and MD simulation; single lab, orthogonal methods","pmids":["39684770"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Atomistic molecular dynamics simulation, Markov thin-filament model, in vitro motility assay, adenoviral expression in human engineered heart tissues, isometric twitch force measurement","journal":"Frontiers in physiology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — integrated simulation and experimental pipeline with human cardiac tissue validation; multiple orthogonal methods converging on mechanism","pmids":["39282088"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Biochemical characterization of recombinant isoforms (thermal stability, F-actin binding, actin filament stiffness via optical trap)","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical assays on multiple isoforms; single lab","pmids":["34067970"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Whole exome sequencing, CRISPR knock-in mouse models, iPSC-derived cardiomyocyte functional assays, genetic suppressor analysis","journal":"Cell reports. Medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — CRISPR KI animal model with rescue experiment, iPSC-derived cardiomyocytes, genetic epistasis across species; rigorous multi-method study","pmids":["35243414"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Immunoprecipitation (TSPAN4-TPM1 interaction), Western blot, EdU proliferation assay, Transwell migration assay, carotid artery ligation in TSPAN4-deficient mice","journal":"Clinical science (London, England : 1979)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing TSPAN4-TPM1 interaction with in vivo mouse model validation; single lab","pmids":["41004162"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Extracellular vesicle isolation and characterization, Western blot, immunohistochemistry, immunofluorescence, transmission electron microscopy for autophagy, proteomic and transcriptomic sequencing","journal":"Lipids in health and disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EV transfer mechanism established with multiple biochemical methods; single lab","pmids":["40221727"],"is_preprint":false},{"year":2026,"finding":"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.","method":"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","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — RNA pulldown/MS, genetic mouse models, iPSC-cardiomyocytes and rescue experiments with multiple orthogonal approaches in one study","pmids":["42261667"],"is_preprint":false},{"year":2026,"finding":"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.","method":"3D protein modeling, AC16 cardiomyocyte transfection, Rhod-2 AM calcium imaging, Phalloidin-488 F-actin staining, Western blot for CaMKII/HDAC4 phosphorylation, qPCR","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cellular assays in cardiomyocytes; single lab, single paper","pmids":["41568329"],"is_preprint":false},{"year":2026,"finding":"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.","method":"Multiomics profiling of rd10 mice, Tpm1 genetic ablation and overexpression, immunofluorescence, Western blot, phagocytosis assays, lipid droplet analysis","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO and overexpression with multiomics and multiple cellular readouts; single lab","pmids":["42202020"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Conditional knockout mice (Cdh5-Cre and Vav-Cre), platelet lifespan assays, platelet adhesion assays (fibronectin, fibrinogen), clot contraction assay, ferric chloride-induced stroke model","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with multiple platelet functional assays and in vivo thrombosis model; preprint, single lab","pmids":["bio_10.1101_2025.07.31.667883"],"is_preprint":true},{"year":2024,"finding":"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.","method":"Recombinant protein biochemical characterization, co-sedimentation assays, optical trap stiffness measurement, thermal stability assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct in vitro biochemical assays with optical trap; single lab","pmids":["38999987"],"is_preprint":false},{"year":2025,"finding":"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).","method":"Co-sedimentation assay, viscometry for actin depolymerization/severing, rhodamine-phalloidin displacement assay","journal":"Biochemistry. Biokhimiia","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — multiple in vitro biochemical assays with five isoforms compared; single lab","pmids":["41067737"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Co-IP assay (TPM1-YAP1), Western blot, RT-qPCR, CCK-8, flow cytometry, scratch healing, Transwell assay","journal":"Discover oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP establishing interaction with functional rescue experiments; single lab","pmids":["40515937"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Immunofluorescence localization in human fibroblasts and SK-N-SH cells, pharmacological compound treatment and washout, isoform-specific localization assays","journal":"Cytoskeleton (Hoboken, N.J.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with pharmacological perturbation establishing isoform-specific cytoskeletal compartmentalization; single lab","pmids":["41085091"],"is_preprint":false},{"year":2026,"finding":"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.","method":"MeRIP (methylated RNA immunoprecipitation), RIP, mRNA stability assay, siRNA knockdown, xenograft model, co-culture macrophage polarization assay","journal":"Cell biology and toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP and RIP directly establish m6A-mediated mRNA regulation; single lab with in vivo validation","pmids":["42215832"],"is_preprint":false},{"year":2026,"finding":"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.","method":"RNA pulldown, proteomic analysis, RNA immunoprecipitation, alternative splicing analysis, gain- and loss-of-function assays, ChIP, luciferase assay","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pulldown/proteomics establishing scaffold mechanism, splicing analysis; single lab","pmids":["41808072"],"is_preprint":false},{"year":2025,"finding":"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.","method":"ChIP assay (ELF3 binding to TPM1 promoter), Western blot, RT-qPCR, CCK-8, clone formation, immunohistochemistry, subcutaneous xenograft","journal":"Cytotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP directly establishes ELF3-TPM1 promoter interaction; single lab","pmids":["40611880"],"is_preprint":false}],"current_model":"TPM1 encodes α-tropomyosin, an actin-stabilizing coiled-coil protein that binds F-actin filaments in a head-to-tail polymer, regulating actin-myosin interactions in a Ca2+-dependent manner in striated muscle; N-terminal acetylation by the NatB complex (via Mdm20p) is required for full F-actin binding activity, and numerous disease-causing point mutations alter tropomyosin positioning on actin, Ca2+ sensitivity of myosin ATPase, and crossbridge cycling to drive hypertrophic or dilated cardiomyopathy through distinct mechanistic pathways; TPM1 also acts as a cytoskeletal organizer in non-muscle cells where it protects actin filaments from cofilin-mediated severing, regulates vesicle transport, platelet adhesion and clot contraction, and modulates inflammatory signaling (TREM2/PKA/CREB and LGALS9/CD45 pathways); its expression is suppressed post-transcriptionally by miR-21 and epigenetically by EZH2/lncRNA complexes in multiple cancer contexts, and alternative splicing of TPM1 exons (regulated by PTB, MBNL1, SRPK3, and other splicing factors) generates functionally distinct isoforms relevant to smooth muscle identity, myofibroblast differentiation, and heart failure."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1992,"claim":"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","pmids":["1629236"],"confidence":"High","gaps":["Does not address mammalian striated-muscle function","Mechanism of myosin-tropomyosin coordination on cables not resolved"]},{"year":1995,"claim":"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","pmids":["7844152"],"confidence":"High","gaps":["Molecular basis of the spacing difference (4 vs 5 monomers) not structurally defined","Relevance to mammalian isoforms untested here"]},{"year":2003,"claim":"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)","pmids":["12808144","11014803"],"confidence":"High","gaps":["Whether mammalian TPM1 isoforms have the same acetylation dependence not shown","Structural basis of acetylation-enhanced binding not resolved"]},{"year":2008,"claim":"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","pmids":["19037011"],"confidence":"Medium","gaps":["Functional consequence of the regulated isoform not addressed","Single-lab reporter system"]},{"year":2013,"claim":"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","pmids":["23511971"],"confidence":"High","gaps":["In vivo physiological output of this exon choice not quantified","Tissue-specificity of the MBNL/PTB complex not mapped"]},{"year":2007,"claim":"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","pmids":["17363372"],"confidence":"High","gaps":["Which TPM1 isoforms mediate growth suppression not resolved","Downstream actin-dependent tumor-suppressive mechanism not defined here"]},{"year":2014,"claim":"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","pmids":["25548289","21376702","22155441","21741356","27480605"],"confidence":"High","gaps":["Did not connect biochemistry to whole-tissue contractile output","Structural states inferred indirectly"]},{"year":2018,"claim":"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","pmids":["30532204"],"confidence":"Medium","gaps":["Performed on skeletal Tpm1.1 only","Methodology paper, limited isoform comparison"]},{"year":2024,"claim":"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)","pmids":["34319370","36896133","39436707","39282088","39684770"],"confidence":"High","gaps":["Long-term in vivo effects of modulators not addressed","Genotype-specific clinical thresholds not defined"]},{"year":2022,"claim":"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","pmids":["35243414"],"confidence":"High","gaps":["Molecular basis of TLN2 suppression of TPM1 not resolved","Mechanism linking myofibril disassembly to ASD not defined"]},{"year":2025,"claim":"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","pmids":["34067970","38999987","41067737","41085091"],"confidence":"Medium","gaps":["In vivo contribution of each isoform to cell migration not quantified","Single-lab biochemical systems"]},{"year":2022,"claim":"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)","pmids":["36241997","35148456","34604206","33661765","40221727","41004162","42202020"],"confidence":"Medium","gaps":["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"]},{"year":2026,"claim":"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","pmids":["37854295","42215832","33499872","40611880","41808072","40515937"],"confidence":"Medium","gaps":["Whether downstream tumor effects require TPM1's actin function not resolved","Isoform identity of regulated transcripts often unspecified"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,3,34,25,33]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[26,24,20]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,9,34,22]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,16,36,34]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[25,33,36]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[16,32]}],"pathway":[{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[7,9,22,24]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[8,19,37,29,38]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[13,22,26,30]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[17,31,37]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0]}],"complexes":[],"partners":["ACT1","MYO2","TLN2","YAP1","TSPAN4","PTB","MBNL1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P09493","full_name":"Tropomyosin alpha-1 chain","aliases":["Alpha-tropomyosin","Tropomyosin-1"],"length_aa":284,"mass_kda":32.7,"function":"Binds to actin filaments in muscle and non-muscle cells (PubMed:23170982). Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction (PubMed:23170982). Smooth muscle contraction is regulated by interaction with caldesmon. In non-muscle cells is implicated in stabilizing cytoskeleton actin filaments","subcellular_location":"Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/P09493/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TPM1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TPM1","total_profiled":1310},"omim":[{"mim_id":"616112","title":"LEIOMODIN 3; LMOD3","url":"https://www.omim.org/entry/616112"},{"mim_id":"615396","title":"LEFT VENTRICULAR NONCOMPACTION 10; LVNC10","url":"https://www.omim.org/entry/615396"},{"mim_id":"613874","title":"CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 18; CMH18","url":"https://www.omim.org/entry/613874"},{"mim_id":"611878","title":"CARDIOMYOPATHY, DILATED, 1Y; CMD1Y","url":"https://www.omim.org/entry/611878"},{"mim_id":"611407","title":"CARDIOMYOPATHY, DILATED, 1W; CMD1W","url":"https://www.omim.org/entry/611407"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Actin filaments","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"heart muscle","ntpm":10511.2},{"tissue":"skeletal muscle","ntpm":11880.5}],"url":"https://www.proteinatlas.org/search/TPM1"},"hgnc":{"alias_symbol":[],"prev_symbol":["C15orf13","CMH3"]},"alphafold":{"accession":"P09493","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P09493","model_url":"https://alphafold.ebi.ac.uk/files/AF-P09493-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P09493-F1-predicted_aligned_error_v6.png","plddt_mean":91.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TPM1","jax_strain_url":"https://www.jax.org/strain/search?query=TPM1"},"sequence":{"accession":"P09493","fasta_url":"https://rest.uniprot.org/uniprotkb/P09493.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P09493/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P09493"}},"corpus_meta":[{"pmid":"17363372","id":"PMC_17363372","title":"MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1).","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17363372","citation_count":880,"is_preprint":false},{"pmid":"20215591","id":"PMC_20215591","title":"Coding sequence rare variants identified in MYBPC3, MYH6, TPM1, TNNC1, and TNNI3 from 312 patients with familial or idiopathic dilated cardiomyopathy.","date":"2010","source":"Circulation. 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America","url":"https://pubmed.ncbi.nlm.nih.gov/12808144","citation_count":88,"is_preprint":false},{"pmid":"19150014","id":"PMC_19150014","title":"[Mutations in sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in patients with hypertrophic cardiomyopathy].","date":"2009","source":"Revista espanola de cardiologia","url":"https://pubmed.ncbi.nlm.nih.gov/19150014","citation_count":59,"is_preprint":false},{"pmid":"30461333","id":"PMC_30461333","title":"Long non-coding RNA MEG3 suppresses the development of bladder urothelial carcinoma by regulating miR-96 and TPM1.","date":"2018","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30461333","citation_count":48,"is_preprint":false},{"pmid":"12651045","id":"PMC_12651045","title":"Variable clinical manifestation of a novel missense mutation in the alpha-tropomyosin (TPM1) gene in familial hypertrophic cardiomyopathy.","date":"2003","source":"Journal of the American College of Cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/12651045","citation_count":44,"is_preprint":false},{"pmid":"37854295","id":"PMC_37854295","title":"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.","date":"2023","source":"Research (Washington, D.C.)","url":"https://pubmed.ncbi.nlm.nih.gov/37854295","citation_count":44,"is_preprint":false},{"pmid":"28754317","id":"PMC_28754317","title":"Natural antisense transcript TPM1-AS regulates the alternative splicing of tropomyosin I through an interaction with RNA-binding motif protein 4.","date":"2017","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28754317","citation_count":43,"is_preprint":false},{"pmid":"25548289","id":"PMC_25548289","title":"Mechanistic heterogeneity in contractile properties of α-tropomyosin (TPM1) mutants 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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.\",\n      \"method\": \"Genetic disruption, secretory pathway epistasis with sec mutants, synthetic lethality with myo2-66, secretion timing assays, electron microscopy of vesicle accumulation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genetic epistasis experiments, multiple secretory pathway mutant combinations, replicated phenotypic readouts\",\n      \"pmids\": [\"1629236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"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.\",\n      \"method\": \"Protein purification and biochemical characterization, F-actin competition assays, genetic double-mutant lethality, overexpression complementation assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro biochemical assays combined with multiple genetic analyses in one study\",\n      \"pmids\": [\"7844152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"Second-site suppressor screen, genetic analysis of haploid and diploid mdm20 strains, actin cable visualization\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — suppressor screen with multiple alleles and phenotypic rescue, single lab\",\n      \"pmids\": [\"11014803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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      \"method\": \"N-terminal acetylation assay, F-actin binding activity comparison of acetylated vs. unacetylated Tpm1p, genetic epistasis between mdm20 and nat3 mutants\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — biochemical acetylation assay, F-actin binding comparison, and genetic epistasis in one study; directly establishes writer (NatB/Nat3p via Mdm20p) and functional consequence\",\n      \"pmids\": [\"12808144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"2D-DIGE proteomics, luciferase 3'-UTR reporter assay with binding site deletion, Western blot, RT-qPCR, anchorage-independent growth assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (reporter assay with deletion mutation, Western blot, functional growth assay) in one study; widely replicated finding across subsequent papers\",\n      \"pmids\": [\"17363372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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).\",\n      \"method\": \"Mutagenesis of cis-acting elements, splicing reporter assays, binding predictions validated by mutational analysis\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic mutagenesis with computational prediction validation, single lab\",\n      \"pmids\": [\"19037011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Reconstituted ghost muscle fiber system with fluorescently labeled actin (Cys374) and myosin S1 (Cys707), polarized fluorimetry during ATPase cycle\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution with fluorescence polarimetry, single lab, single paper\",\n      \"pmids\": [\"21741356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Fluorescently labeled recombinant tropomyosins incorporated into ghost muscle fibers, polarized fluorimetry during ATPase cycle stages\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with polarized fluorimetry; two mutations tested in same study providing orthogonal comparison\",\n      \"pmids\": [\"21376702\", \"22155441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"RNA binding assays, protein-protein interaction assays, single molecule analysis of PTB binding, domain deletion mutagenesis of MBNL1, splicing reporter assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (binding assays, protein interaction, single molecule analysis, mutagenesis) establishing mechanism in one study\",\n      \"pmids\": [\"23511971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Ca2+ sensitivity of human β-cardiac myosin ATPase activity measurements, fluorescent probe monitoring of TnC conformational changes, protein stability assays, protein-protein interaction assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple biochemical assays on seven mutants in one study, with functional readout directly linked to cardiomyopathy mechanism\",\n      \"pmids\": [\"25548289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with three different mutants providing comparative mechanistic data, single lab\",\n      \"pmids\": [\"27480605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Single molecule fluorescence TIRF microscopy with microfluidic device, fluorescently labeled Tpm1.1 on single actin filaments, kymograph analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct in vitro single molecule assay establishing kinetic parameters; single lab, methodology paper\",\n      \"pmids\": [\"30532204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Review integrating functional mutation studies; mechanistic findings derive from cited experimental work on actin-myosin ATPase, pointed end regulation assays\",\n      \"journal\": \"Journal of muscle research and cell motility\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review paper integrating prior experimental data; no new primary experiments reported in this abstract\",\n      \"pmids\": [\"31270709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Molecular dynamics simulation, in vitro motility assay, multiscale computational modeling, patient-derived iPSC-engineered heart tissues, mavacamten pharmacological rescue\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (MD, in vitro assay, patient-derived cardiac tissues, pharmacological rescue) in one study establishing mechanism\",\n      \"pmids\": [\"34319370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LINC01116 recruits EZH2 to the TPM1 promoter, resulting in H3K27me3-mediated transcriptional silencing of TPM1, thereby promoting colorectal cancer cell proliferation and angiogenesis.\",\n      \"method\": \"RNA pull-down, RIP assay, ChIP assay for EZH2 and H3K27me3 at TPM1 promoter, xenograft model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and RIP assays establish EZH2 recruitment to TPM1 promoter, single lab with in vivo validation\",\n      \"pmids\": [\"33499872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Transgenic mouse (Cre-loxP), siRNA knockdown of TPM1, BrdU incorporation for proliferation, FACS and image analysis for hypertrophy\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic model with siRNA validation distinguishing proliferation vs. hypertrophy roles, single lab\",\n      \"pmids\": [\"33661765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPRa transcriptional activation of endogenous TPM1, immunofluorescence of F-actin and junctional proteins, Western blot for VE-cadherin/catenins, migration assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPRa with multiple cellular readouts; single lab, orthogonal assays\",\n      \"pmids\": [\"34604206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"TPM1 siRNA knockdown in WT and TREM2-/- retinas, RNA sequencing, immunocytochemistry, Western blot, qPCR, TUNEL, electroretinogram, CX3CR1CreER:Rosa26iDTR microglia depletion model\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO model with RNA-seq and multiple orthogonal readouts; pathway placement by epistasis; single lab\",\n      \"pmids\": [\"36241997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Heterochronic parabiosis, plasma transfer, recombinant TPM1 protein administration, anti-TPM1 neutralizing antibody treatment, proteomic analysis, Western blot, PKA phosphorylation assays\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vivo models (parabiosis, plasma, recombinant protein, neutralizing antibody) establishing systemic signaling role; single lab\",\n      \"pmids\": [\"35148456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"RNA pull-down with mass spectrometry, co-immunoprecipitation, RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation (MeRIP), xenograft mouse model, patient-derived organoids\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods (pull-down MS, Co-IP, RIP, MeRIP) establishing the AZGP1P2/UBA1/RBM15/TPM1 axis; single lab\",\n      \"pmids\": [\"37854295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Molecular dynamics simulation, Markov model of thin filament activation, in vitro motility assay, 3D genetically engineered heart tissues (iPSC-derived cardiomyocytes)\",\n      \"journal\": \"PNAS nexus\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — integrated computational and experimental pipeline with in vitro motility and patient-relevant engineered tissue; orthogonal methods converging on same mechanism\",\n      \"pmids\": [\"36896133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"TMT quantitative proteomics, Western blot for CaMKII phosphorylation (Thr287), KN-93 pharmacological inhibition in vitro and in vivo (rat ECG)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics combined with pharmacological rescue in vitro and in vivo; single lab\",\n      \"pmids\": [\"37037889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Computational thin-filament simulations, iPSC-derived cardiomyocytes engineered heart tissues, myosin modulator pharmacological rescue, gene expression analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — integrated computational and experimental approach with patient-derived cardiac tissues and pharmacological validation; two mutations with distinct mechanistic explanations confirmed orthogonally\",\n      \"pmids\": [\"39436707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Recombinant protein production, biochemical stability assays, in vitro motility assay, molecular dynamics simulation\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with motility assay and MD simulation; single lab, orthogonal methods\",\n      \"pmids\": [\"39684770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Atomistic molecular dynamics simulation, Markov thin-filament model, in vitro motility assay, adenoviral expression in human engineered heart tissues, isometric twitch force measurement\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — integrated simulation and experimental pipeline with human cardiac tissue validation; multiple orthogonal methods converging on mechanism\",\n      \"pmids\": [\"39282088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Biochemical characterization of recombinant isoforms (thermal stability, F-actin binding, actin filament stiffness via optical trap)\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical assays on multiple isoforms; single lab\",\n      \"pmids\": [\"34067970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Whole exome sequencing, CRISPR knock-in mouse models, iPSC-derived cardiomyocyte functional assays, genetic suppressor analysis\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — CRISPR KI animal model with rescue experiment, iPSC-derived cardiomyocytes, genetic epistasis across species; rigorous multi-method study\",\n      \"pmids\": [\"35243414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Immunoprecipitation (TSPAN4-TPM1 interaction), Western blot, EdU proliferation assay, Transwell migration assay, carotid artery ligation in TSPAN4-deficient mice\",\n      \"journal\": \"Clinical science (London, England : 1979)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing TSPAN4-TPM1 interaction with in vivo mouse model validation; single lab\",\n      \"pmids\": [\"41004162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Extracellular vesicle isolation and characterization, Western blot, immunohistochemistry, immunofluorescence, transmission electron microscopy for autophagy, proteomic and transcriptomic sequencing\",\n      \"journal\": \"Lipids in health and disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EV transfer mechanism established with multiple biochemical methods; single lab\",\n      \"pmids\": [\"40221727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — RNA pulldown/MS, genetic mouse models, iPSC-cardiomyocytes and rescue experiments with multiple orthogonal approaches in one study\",\n      \"pmids\": [\"42261667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"3D protein modeling, AC16 cardiomyocyte transfection, Rhod-2 AM calcium imaging, Phalloidin-488 F-actin staining, Western blot for CaMKII/HDAC4 phosphorylation, qPCR\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cellular assays in cardiomyocytes; single lab, single paper\",\n      \"pmids\": [\"41568329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"Multiomics profiling of rd10 mice, Tpm1 genetic ablation and overexpression, immunofluorescence, Western blot, phagocytosis assays, lipid droplet analysis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and overexpression with multiomics and multiple cellular readouts; single lab\",\n      \"pmids\": [\"42202020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional knockout mice (Cdh5-Cre and Vav-Cre), platelet lifespan assays, platelet adhesion assays (fibronectin, fibrinogen), clot contraction assay, ferric chloride-induced stroke model\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with multiple platelet functional assays and in vivo thrombosis model; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.07.31.667883\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Recombinant protein biochemical characterization, co-sedimentation assays, optical trap stiffness measurement, thermal stability assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro biochemical assays with optical trap; single lab\",\n      \"pmids\": [\"38999987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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).\",\n      \"method\": \"Co-sedimentation assay, viscometry for actin depolymerization/severing, rhodamine-phalloidin displacement assay\",\n      \"journal\": \"Biochemistry. Biokhimiia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple in vitro biochemical assays with five isoforms compared; single lab\",\n      \"pmids\": [\"41067737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP assay (TPM1-YAP1), Western blot, RT-qPCR, CCK-8, flow cytometry, scratch healing, Transwell assay\",\n      \"journal\": \"Discover oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP establishing interaction with functional rescue experiments; single lab\",\n      \"pmids\": [\"40515937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Immunofluorescence localization in human fibroblasts and SK-N-SH cells, pharmacological compound treatment and washout, isoform-specific localization assays\",\n      \"journal\": \"Cytoskeleton (Hoboken, N.J.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with pharmacological perturbation establishing isoform-specific cytoskeletal compartmentalization; single lab\",\n      \"pmids\": [\"41085091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"MeRIP (methylated RNA immunoprecipitation), RIP, mRNA stability assay, siRNA knockdown, xenograft model, co-culture macrophage polarization assay\",\n      \"journal\": \"Cell biology and toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP and RIP directly establish m6A-mediated mRNA regulation; single lab with in vivo validation\",\n      \"pmids\": [\"42215832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"RNA pulldown, proteomic analysis, RNA immunoprecipitation, alternative splicing analysis, gain- and loss-of-function assays, ChIP, luciferase assay\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pulldown/proteomics establishing scaffold mechanism, splicing analysis; single lab\",\n      \"pmids\": [\"41808072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP assay (ELF3 binding to TPM1 promoter), Western blot, RT-qPCR, CCK-8, clone formation, immunohistochemistry, subcutaneous xenograft\",\n      \"journal\": \"Cytotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP directly establishes ELF3-TPM1 promoter interaction; single lab\",\n      \"pmids\": [\"40611880\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TPM1 encodes α-tropomyosin, an actin-stabilizing coiled-coil protein that binds F-actin filaments in a head-to-tail polymer, regulating actin-myosin interactions in a Ca2+-dependent manner in striated muscle; N-terminal acetylation by the NatB complex (via Mdm20p) is required for full F-actin binding activity, and numerous disease-causing point mutations alter tropomyosin positioning on actin, Ca2+ sensitivity of myosin ATPase, and crossbridge cycling to drive hypertrophic or dilated cardiomyopathy through distinct mechanistic pathways; TPM1 also acts as a cytoskeletal organizer in non-muscle cells where it protects actin filaments from cofilin-mediated severing, regulates vesicle transport, platelet adhesion and clot contraction, and modulates inflammatory signaling (TREM2/PKA/CREB and LGALS9/CD45 pathways); its expression is suppressed post-transcriptionally by miR-21 and epigenetically by EZH2/lncRNA complexes in multiple cancer contexts, and alternative splicing of TPM1 exons (regulated by PTB, MBNL1, SRPK3, and other splicing factors) generates functionally distinct isoforms relevant to smooth muscle identity, myofibroblast differentiation, and heart failure.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #34]. 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 [#0, #1]; full F-actin binding activity depends on N-terminal acetylation by the NatB complex, which requires Mdm20p acting cooperatively with the catalytic subunit Nat3p [#3, #2]. 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 [#7, #9, #22, #6]. 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 [#13, #20, #24, #22]. 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 [#8, #25, #33, #29]. 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 [#34, #36, #16]. 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 [#4, #19, #37, #14, #39]. 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 [#26].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"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.\",\n      \"evidence\": \"Yeast TPM1 gene disruption with secretory-pathway epistasis (sec mutants) and synthetic lethality with myo2\",\n      \"pmids\": [\"1629236\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address mammalian striated-muscle function\", \"Mechanism of myosin-tropomyosin coordination on cables not resolved\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Showed that distinct tropomyosins occupy different filament periodicities and are non-redundant, establishing that tropomyosin isoform identity, not just presence, determines function.\",\n      \"evidence\": \"Protein purification, F-actin competition assays, and double-mutant lethality in yeast\",\n      \"pmids\": [\"7844152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the spacing difference (4 vs 5 monomers) not structurally defined\", \"Relevance to mammalian isoforms untested here\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified an upstream post-translational requirement for tropomyosin activity, showing N-terminal acetylation by NatB licenses F-actin binding.\",\n      \"evidence\": \"N-terminal acetylation assay, acetylated vs unacetylated F-actin binding comparison, mdm20/nat3 epistasis in yeast (building on 2000 suppressor screen)\",\n      \"pmids\": [\"12808144\", \"11014803\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mammalian TPM1 isoforms have the same acetylation dependence not shown\", \"Structural basis of acetylation-enhanced binding not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined cis- and trans-acting control of a TPM1 splicing decision, opening the mechanism by which isoform diversity is generated.\",\n      \"evidence\": \"Mutagenesis of cis-elements and splicing reporter assays in rat Tpm1, with hnRNP H/F and MBNL/PTB\",\n      \"pmids\": [\"19037011\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the regulated isoform not addressed\", \"Single-lab reporter system\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established MBNL1 as an allosteric repressor that cooperates with PTB to control Tpm1 exon inclusion, explaining combinatorial splicing regulation.\",\n      \"evidence\": \"RNA binding, protein-protein interaction, single-molecule and domain-deletion analyses with splicing reporters\",\n      \"pmids\": [\"23511971\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo physiological output of this exon choice not quantified\", \"Tissue-specificity of the MBNL/PTB complex not mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified TPM1 as a translationally repressed miR-21 target and a tumor-suppressive cytoskeletal regulator, linking its downregulation to transformed phenotypes.\",\n      \"evidence\": \"3'-UTR luciferase reporter with binding-site deletion, Western blot, anchorage-independent growth assay in breast cancer cells\",\n      \"pmids\": [\"17363372\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which TPM1 isoforms mediate growth suppression not resolved\", \"Downstream actin-dependent tumor-suppressive mechanism not defined here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"evidence\": \"Ca2+-dependent β-cardiac myosin ATPase, TnC conformational probes, stability and interaction assays on seven mutants\",\n      \"pmids\": [\"25548289\", \"21376702\", \"22155441\", \"21741356\", \"27480605\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect biochemistry to whole-tissue contractile output\", \"Structural states inferred indirectly\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Quantified tropomyosin assembly kinetics on single actin filaments, grounding regulatory models in measured nucleation, elongation, and dissociation rates.\",\n      \"evidence\": \"Single-molecule TIRF microscopy with microfluidics and kymograph analysis\",\n      \"pmids\": [\"30532204\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Performed on skeletal Tpm1.1 only\", \"Methodology paper, limited isoform comparison\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected molecular-scale tropomyosin defects to tissue-level contractile dysfunction and pharmacological rescue, validating excess/deficient crossbridge activity as the pathogenic axis.\",\n      \"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)\",\n      \"pmids\": [\"34319370\", \"36896133\", \"39436707\", \"39282088\", \"39684770\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term in vivo effects of modulators not addressed\", \"Genotype-specific clinical thresholds not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided direct Mendelian evidence that TPM1 is required for myofibril assembly and cardiac morphogenesis, with a genetic modifier explaining variable lethality.\",\n      \"evidence\": \"Five-generation pedigree exome sequencing, CRISPR knock-in mouse rescue with TLN2, and iPSC-derived cardiomyocytes\",\n      \"pmids\": [\"35243414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of TLN2 suppression of TPM1 not resolved\", \"Mechanism linking myofibril disassembly to ASD not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined functionally distinct cytoplasmic TPM1 isoforms that protect actin from cofilin severing and localize to specific cytoskeletal compartments, establishing isoform-specific non-muscle roles.\",\n      \"evidence\": \"Recombinant isoform biochemistry (co-sedimentation, optical-trap stiffness, cofilin protection) and isoform-specific lamellipodial localization with pharmacological perturbation\",\n      \"pmids\": [\"34067970\", \"38999987\", \"41067737\", \"41085091\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo contribution of each isoform to cell migration not quantified\", \"Single-lab biochemical systems\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"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)\",\n      \"pmids\": [\"36241997\", \"35148456\", \"34604206\", \"33661765\", \"40221727\", \"41004162\", \"42202020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established multilayered post-transcriptional and transcriptional control of TPM1 abundance (m6A, lncRNA/EZH2, ELF3, circRNA-driven splicing) tying its repression to cancer progression.\",\n      \"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\",\n      \"pmids\": [\"37854295\", \"42215832\", \"33499872\", \"40611880\", \"41808072\", \"40515937\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether downstream tumor effects require TPM1's actin function not resolved\", \"Isoform identity of regulated transcripts often unspecified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 3, 34, 25, 33]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [26, 24, 20]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 9, 34, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 16, 36, 34]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [25, 33, 36]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [16, 32]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [7, 9, 22, 24]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [8, 19, 37, 29, 38]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [13, 22, 26, 30]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [17, 31, 37]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ACT1\",\n      \"MYO2\",\n      \"TLN2\",\n      \"YAP1\",\n      \"TSPAN4\",\n      \"PTB\",\n      \"MBNL1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}