TPM3 (Tropomyosin 3) is a coiled-coil actin-binding protein with 7 tissue-specific isoforms. ISOFORM BIOLOGY: (1) Isoform 1 (P06753-1) is expressed in SLOW SKELETAL MUSCLE (type I fibers); (2) Isoform 2 (TM30nm, P06753-2) is the shorter CYTOSKELETAL form (248 AA vs 285 AA for muscle). The muscle isoform is part of the thin filament regulatory complex essential for muscle contraction in slow-twitch fibers. The cytoskeletal TM30nm variant has different actin binding properties and functions in non-muscle cells. DISEASE: Mutations cause Congenital myopathy 4A (CMYO4A) with nemaline rods, cap structures, and fiber-type disproportion. Annotations for "muscle contraction" apply to muscle isoforms; "actin cytoskeleton" applies primarily to cytoskeletal isoforms.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0051015 actin filament binding | IBA GO_REF:0000033 | ACCEPT | Summary: TPM3 is a well-established actin-binding protein. UniProt states "Binds to actin filaments in muscle and non-muscle cells" [UniProt P06753]. Both the muscle isoform (285 AA) and cytoskeletal TM30nm isoform (248 AA) bind actin filaments, though with different properties. PMID:3018581 confirms tissue-specific expression with "a 2.5-kilobase (kb) mRNA encoding a 248-amino-acid tropomyosin in human fibroblasts" (cytoskeletal) and "a 1.3-kb mRNA encoding a 285-amino-acid tropomyosin in human skeletal muscle." This is a core molecular function shared across all isoforms. Reason: Actin filament binding is a fundamental molecular function of all tropomyosin isoforms. The IBA annotation is well-supported by the phylogenetic conservation of this function across the tropomyosin family and direct experimental evidence from multiple studies. This represents a core function of TPM3. Supporting Evidence: PMID:3018581 a 2.5-kilobase (kb) mRNA encoding a 248-amino-acid tropomyosin in human fibroblasts and a 1.3-kb mRNA encoding a 285-amino-acid tropomyosin in human skeletal muscle file:human/TPM3/TPM3-uniprot.txt Binds to actin filaments in muscle and non-muscle cells file:human/TPM3/TPM3-deep-research-falcon.md Falcon report emphasizes TPM3 actin-filament binding/stabilization, isoform-specific actin filament identity, and thin-filament regulation in muscle. |
| GO:0007015 actin filament organization | IBA GO_REF:0000033 | ACCEPT | Summary: TPM3 contributes to actin filament organization in both muscle and non-muscle contexts. UniProt states that in non-muscle cells TPM3 is implicated in stabilizing cytoskeleton actin filaments, while the muscle isoform contributes to thin-filament regulation. This process annotation appropriately captures the conserved role of tropomyosins in organizing actin filament architecture. Reason: Actin filament organization is a well-supported biological process for TPM3. The IBA annotation reflects the conserved role of tropomyosins in organizing and stabilizing actin filament structures. This applies to both muscle (thin filament organization) and non-muscle (cytoskeletal) isoforms, representing a core function of the gene. Supporting Evidence: file:human/TPM3/TPM3-uniprot.txt In non-muscle cells is implicated in stabilizing cytoskeleton actin filaments file:human/TPM3/TPM3-deep-research-falcon.md Falcon report emphasizes TPM3 actin-filament binding/stabilization, isoform-specific actin filament identity, and thin-filament regulation in muscle. |
| GO:0005884 actin filament | IBA GO_REF:0000033 | ACCEPT | Summary: TPM3 localizes to actin filaments as an integral component. Tropomyosins are coiled-coil proteins that bind along the length of actin filaments. UniProt confirms "Binds to actin filaments in muscle and non-muscle cells" [UniProt P06753]. In muscle, TPM3 is part of the thin filament; in non-muscle cells, it decorates cytoskeletal actin filaments. This localization is fundamental to tropomyosin function. Reason: Actin filament is the correct cellular component for TPM3 localization. This is a core structural feature of tropomyosins - they bind along the entire length of actin filaments as coiled-coil dimers. The IBA annotation is phylogenetically well-supported across the tropomyosin family. Supporting Evidence: file:human/TPM3/TPM3-uniprot.txt Binds to actin filaments in muscle and non-muscle cells file:human/TPM3/TPM3-deep-research-falcon.md Falcon report emphasizes TPM3 actin-filament binding/stabilization, isoform-specific actin filament identity, and thin-filament regulation in muscle. |
| GO:0006936 muscle contraction | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Muscle contraction is a function specific to TPM3 Isoform 1 (skeletal muscle isoform, 285 AA). UniProt states TPM3 "Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction" [UniProt P06753]. The cytoskeletal isoforms (TM30nm) do not participate in muscle contraction. TPM3 Isoform 1 is expressed in slow-twitch (type I) skeletal muscle fibers. Disease mutations causing CMYO4A demonstrate the importance of this function. Reason: Muscle contraction is valid for the skeletal muscle isoform (Isoform 1) but not for cytoskeletal isoforms (Isoform 2/TM30nm and others). Since this annotation applies to only a subset of isoforms expressed in specific tissues, it should be marked as non-core. The core function of TPM3 across all isoforms is actin filament binding and organization, while muscle contraction is tissue/isoform-specific. Supporting Evidence: file:human/TPM3/TPM3-uniprot.txt Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction PMID:3018581 a 1.3-kb mRNA encoding a 285-amino-acid tropomyosin in human skeletal muscle file:human/TPM3/TPM3-deep-research-falcon.md Falcon report emphasizes TPM3 actin-filament binding/stabilization, isoform-specific actin filament identity, and thin-filament regulation in muscle. |
| GO:0003779 actin binding | IEA GO_REF:0000043 | ACCEPT | Summary: This IEA annotation for "actin binding" is derived from UniProt keyword mapping. While technically correct, it is less specific than the IBA annotation for GO:0051015 "actin filament binding" which better captures the mechanism by which TPM3 binds actin (along the filament, not to monomeric actin). Reason: While GO:0051015 "actin filament binding" is more specific and preferred, this broader "actin binding" annotation is not incorrect. TPM3 does bind actin (specifically filamentous actin). The IEA provides complementary support to the more specific IBA annotation. Both can coexist as the more specific term is appropriately annotated via IBA. Supporting Evidence: file:human/TPM3/TPM3-uniprot.txt Binds to actin filaments in muscle and non-muscle cells |
| GO:0005856 cytoskeleton | IEA GO_REF:0000044 | ACCEPT | Summary: This IEA annotation for cytoskeleton localization is derived from UniProt subcellular location mapping. UniProt lists "Cytoplasm, cytoskeleton" as the subcellular location [UniProt P06753]. While correct, more specific terms like "actin filament" (GO:0005884) or "stress fiber" (GO:0001725) better describe the actual localization of TPM3. Reason: The cytoskeleton annotation is a valid but general cellular component term. TPM3 is indeed a cytoskeletal protein, associating with actin filaments in both muscle and non-muscle cells. The more specific IBA annotation to "actin filament" (GO:0005884) provides better granularity, but this broader term is not incorrect. Supporting Evidence: file:human/TPM3/TPM3-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton |
| GO:0005862 muscle thin filament tropomyosin | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: This IEA annotation from ARBA machine learning correctly identifies TPM3 as a component of muscle thin filament tropomyosin. However, this applies specifically to Isoform 1 (skeletal muscle isoform). The cytoskeletal isoforms (TM30nm/Isoform 2) are not part of the muscle thin filament structure. PMID:3018581 and PMID:3418707 clearly describe the tissue-specific alternative splicing that produces distinct muscle and non-muscle isoforms. Reason: This annotation is accurate for the muscle isoform (Isoform 1) but not for cytoskeletal isoforms. The muscle thin filament complex includes tropomyosin in association with troponin for calcium-regulated muscle contraction. Since this is isoform-specific, it represents a non-core function. The core localization applicable to all isoforms is "actin filament" (GO:0005884). Supporting Evidence: PMID:3418707 In muscle, alternative splicing of this gene results in the expression of a 1.3 kb mRNA encoding a 285 amino acid skeletal muscle alpha-tropomyosin file:human/TPM3/TPM3-uniprot.txt Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction file:human/TPM3/TPM3-deep-research-falcon.md Falcon report emphasizes TPM3 actin-filament binding/stabilization, isoform-specific actin filament identity, and thin-filament regulation in muscle. |
| GO:0005515 protein binding | IPI PMID:14743216 A physical and functional map of the human TNF-alpha/NF-kapp... | MARK AS OVER ANNOTATED | Summary: This IPI annotation is from a large-scale TNF-alpha/NF-kappa B signaling pathway mapping study (PMID:14743216). The generic "protein binding" term provides limited functional information about TPM3's specific interactions. TPM3 is known to interact with specific partners including TMOD1, TNNT1, and the troponin complex in muscle [UniProt P06753]. Reason: The term "protein binding" (GO:0005515) is uninformative for GO annotation purposes. While TPM3 clearly interacts with proteins (actin, troponin components, etc.), this generic term does not capture the functional nature of those interactions. More specific molecular function terms like "actin filament binding" (GO:0051015) are already annotated. High-throughput interactome studies often identify many interactions without functional validation. Supporting Evidence: PMID:14743216 A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | MARK AS OVER ANNOTATED | Summary: This annotation from PMID:16189514 (large-scale human protein-protein interaction network mapping) uses the generic "protein binding" term. This is a high-throughput study that identified many interactions without specific functional characterization. Reason: The term "protein binding" is uninformative and considered a bad practice for GO annotation. TPM3's specific protein interactions (actin filaments, troponin complex, TMOD1, TNNT1) are better captured by more specific terms. Large-scale interactome data should ideally be used to generate more specific interaction annotations. Supporting Evidence: PMID:16189514 Towards a proteome-scale map of the human protein-protein interaction network |
| GO:0005515 protein binding | IPI PMID:17353931 Large-scale mapping of human protein-protein interactions by... | MARK AS OVER ANNOTATED | Summary: This annotation from PMID:17353931 (large-scale mapping of human protein-protein interactions by mass spectrometry) uses the generic "protein binding" term from high-throughput interaction data. Reason: The term "protein binding" is uninformative for GO annotation. While TPM3 clearly engages in multiple protein-protein interactions, more specific molecular function terms are preferred. High-throughput mass spectrometry interactome studies provide evidence for interactions but rarely characterize the functional nature of those interactions. Supporting Evidence: PMID:17353931 Large-scale mapping of human protein-protein interactions by mass spectrometry |
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | MARK AS OVER ANNOTATED | Summary: This annotation from PMID:21516116 (next-generation sequencing for interactome datasets) uses the generic "protein binding" term from high-throughput interaction data. Reason: The term "protein binding" is uninformative. TPM3's functionally relevant interactions (with actin filaments, troponin complex components) are better captured by specific terms. Generic protein binding from large-scale interactome studies does not provide mechanistic insight. Supporting Evidence: PMID:21516116 Next-generation sequencing to generate interactome datasets |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: This annotation from PMID:25416956 (proteome-scale map of the human interactome network) uses the generic "protein binding" term from high-throughput interaction data. Reason: The term "protein binding" is uninformative for GO annotation. Large-scale interactome mapping studies identify many interactions but the generic term does not convey functional information about TPM3's specific binding partners or the nature of those interactions. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | MARK AS OVER ANNOTATED | Summary: This annotation from PMID:25910212 (macromolecular interaction perturbations in genetic disorders) uses the generic "protein binding" term. Reason: The term "protein binding" is uninformative. While this study examines disease-relevant interactions, the generic annotation does not capture the specific functional context of TPM3 interactions. Supporting Evidence: PMID:25910212 Widespread macromolecular interaction perturbations in human genetic disorders [interaction perturbation study] |
| GO:0005515 protein binding | IPI PMID:25959826 Quantitative interaction proteomics of neurodegenerative dis... | MARK AS OVER ANNOTATED | Summary: This annotation from PMID:25959826 (interaction proteomics of neurodegenerative disease proteins) uses the generic "protein binding" term from high-throughput interaction data. Reason: The term "protein binding" is uninformative. This study focused on neurodegenerative disease proteins and TPM3 may have been identified as an interaction partner. However, the generic annotation does not provide functional insight. Supporting Evidence: PMID:25959826 Quantitative interaction proteomics of neurodegenerative disease proteins |
| GO:0005515 protein binding | IPI PMID:27107012 Pooled-matrix protein interaction screens using Barcode Fusi... | MARK AS OVER ANNOTATED | Summary: This annotation from PMID:27107012 (Barcode Fusion Genetics pooled-matrix protein interaction screens) uses the generic "protein binding" term. Reason: The term "protein binding" is uninformative. High-throughput screening methods identify many interactions but the generic term does not convey the functional significance of specific TPM3 interactions. Supporting Evidence: PMID:27107012 Pooled-matrix protein interaction screens using Barcode Fusion Genetics |
| GO:0005515 protein binding | IPI PMID:29128334 A Map of Human Mitochondrial Protein Interactions Linked to ... | MARK AS OVER ANNOTATED | Summary: This annotation from PMID:29128334 (mitochondrial protein interactions linked to neurodegeneration) uses the generic "protein binding" term. Reason: The term "protein binding" is uninformative. While this study links mitochondrial interactions to neurodegeneration, the generic annotation does not provide functional insight into TPM3's role. TPM3's primary localization is cytoskeletal/actin filaments, not mitochondrial. Supporting Evidence: PMID:29128334 A Map of Human Mitochondrial Protein Interactions Linked to Neurodegeneration Reveals New Mechanisms of Redox Homeostasis and NF-ΞΊB Signaling |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | MARK AS OVER ANNOTATED | Summary: This annotation from PMID:31515488 (disruption of protein interactions by genetic variants) uses the generic "protein binding" term. Reason: The term "protein binding" is uninformative. While this study examines how genetic variants disrupt protein interactions, the generic annotation does not provide functional insight into specific TPM3 interactions. Supporting Evidence: PMID:31515488 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: This annotation from PMID:32296183 (reference map of the human binary protein interactome) uses the generic "protein binding" term from high-throughput interaction data. Reason: The term "protein binding" is uninformative for GO annotation. Reference interactome maps identify many binary interactions but the generic term does not convey functional significance. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: This annotation from PMID:32814053 (interactome mapping of neurodegenerative disease proteins) uses the generic "protein binding" term. Reason: The term "protein binding" is uninformative. While this study focuses on neurodegeneration-related protein aggregation, the generic annotation does not specify the functional context of any TPM3 interactions identified. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: This annotation from PMID:33961781 (dual proteome-scale networks for cell-specific interactome remodeling) uses the generic "protein binding" term. Reason: The term "protein binding" is uninformative. While this study examines cell-specific interactome remodeling, the generic annotation does not convey functional information about TPM3 interactions. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: This annotation from PMID:40205054 (multimodal cell maps for structural and functional genomics) uses the generic "protein binding" term. Reason: The term "protein binding" is uninformative. Large-scale multimodal cell mapping identifies interactions but the generic annotation does not provide functional insight into TPM3's role. Supporting Evidence: PMID:40205054 Multimodal cell maps as a foundation for structural and functional genomics |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | MARK AS OVER ANNOTATED | Summary: This HTP annotation for mitochondrial localization is from a high-confidence human mitochondrial proteome study (PMID:34800366). However, TPM3's established localization is to actin filaments in the cytoskeleton. UniProt lists "Cytoplasm, cytoskeleton" as the subcellular location. Mitochondrial association may reflect high-throughput detection artifacts or transient/minor localization rather than a core functional site. Reason: TPM3 is primarily a cytoskeletal protein that binds to actin filaments. The mitochondrial localization identified in this high-throughput proteomics study may represent contamination, transient association, or a minor pool of protein. The primary functional localization of TPM3 is to actin filaments (muscle thin filaments or cytoskeletal actin), not mitochondria. This annotation should be viewed with caution. Supporting Evidence: file:human/TPM3/TPM3-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton |
| GO:0005515 protein binding | IPI PMID:35510366 Autosomal dominantly inherited myopathy likely caused by the... | MARK AS OVER ANNOTATED | Summary: PMID:35510366 supports a TPM3-TNNT1 interaction in a muscle thin-filament disease context, but the GO term used here is the generic protein binding term rather than a specific thin-filament or troponin/tropomyosin interaction term. Reason: The interaction is biologically relevant, but GO:0005515 is too generic to accept as a useful TPM3 molecular-function annotation. TPM3 already has specific actin filament binding and muscle thin-filament context annotations; this row should not be treated as core protein-binding function. Supporting Evidence: PMID:35510366 complex formation of TnT1-D65A with tropomyosin 3 (TPM3) was enhanced file:human/TPM3/TPM3-uniprot.txt Interacts with TNNT1 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9700179 | KEEP AS NON CORE | Summary: This Reactome row describes cytosolic signaling context for oncogenic ALK fusion proteins that can use TPM3 as an N-terminal fusion partner, not native TPM3 actin-filament localization. Reason: Keep only as non-core fusion-protein/pathway context. Native TPM3 function is actin-filament binding and cytoskeletal/thin-filament regulation; the ALK fusion Reactome pathways should not be used as primary evidence for normal TPM3 localization. Supporting Evidence: Reactome:R-HSA-9700179 In addition to NPM, fusions with ALK have also been identified with EML4 file:human/TPM3/TPM3-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9700181 | KEEP AS NON CORE | Summary: This Reactome row describes cytosolic signaling context for oncogenic ALK fusion proteins that can use TPM3 as an N-terminal fusion partner, not native TPM3 actin-filament localization. Reason: Keep only as non-core fusion-protein/pathway context. Native TPM3 function is actin-filament binding and cytoskeletal/thin-filament regulation; the ALK fusion Reactome pathways should not be used as primary evidence for normal TPM3 localization. Supporting Evidence: Reactome:R-HSA-9700181 After partner protein-mediated dimerization, ALK fusions are trans-autophosphorylated by the ALK kinase domain file:human/TPM3/TPM3-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton |
| GO:0005515 protein binding | IPI PMID:23892143 Human respiratory syncytial virus N, P and M protein interac... | MARK AS OVER ANNOTATED | Summary: This annotation from PMID:23892143 (RSV N, P and M protein interactions in HEK-293T cells) uses the generic "protein binding" term. This study focused on respiratory syncytial virus protein interactions, and TPM3 may have been identified as a cellular interaction partner. Reason: The term "protein binding" is uninformative. This study examined viral protein interactions and any TPM3 interactions identified likely represent host-pathogen interactions rather than TPM3's core cellular function. The generic annotation provides no functional insight. Supporting Evidence: PMID:23892143 Human respiratory syncytial virus N, P and M protein interactions in HEK-293T cells |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | KEEP AS NON CORE | Summary: This HDA annotation for extracellular exosome localization derives from PMID:20458337, a study of MHC class II-associated proteins in B-cell exosomes. The study "identified 539 proteins" in exosomes from B cells. TPM3 detection in exosomes likely represents packaging of cytoskeletal components into exosomal cargo rather than a core functional localization. Reason: Detection of TPM3 in extracellular exosomes represents exosomal cargo packaging rather than a site of TPM3 function. Cytoskeletal proteins are commonly found in exosome proteomes. This is a valid observation but does not represent a core functional localization for TPM3, which primarily functions on actin filaments in the cytoskeleton. Supporting Evidence: PMID:20458337 we first analyzed the total proteome of highly purified B cell-derived exosomes using sensitive and accurate mass spectrometry (MS), and identified 539 proteins |
| GO:0005829 cytosol | TAS Reactome:R-HSA-390593 | KEEP AS NON CORE | Summary: This cytosol annotation derives from a Reactome muscle contraction pathway step. It is compatible with TPM3-containing thin-filament complexes but is less informative than actin filament, muscle thin filament tropomyosin, or cytoskeleton localization. Reason: Keep cytosol as non-core pathway context because TPM3 is a cytoskeletal/thin-filament actin-binding protein. The specific functional locations are actin filament, muscle thin filament tropomyosin, cytoskeleton, and, where directly supported, stress-fiber/cytoskeletal structures. Supporting Evidence: Reactome:R-HSA-390593 The cleft closes like a clam shell around the ATP molecule, triggering a large shape change that causes the myosin head to release actin |
| GO:0005829 cytosol | TAS Reactome:R-HSA-390595 | KEEP AS NON CORE | Summary: This cytosol annotation derives from a Reactome muscle contraction pathway step. It is compatible with TPM3-containing thin-filament complexes but is less informative than actin filament, muscle thin filament tropomyosin, or cytoskeleton localization. Reason: Keep cytosol as non-core pathway context because TPM3 is a cytoskeletal/thin-filament actin-binding protein. The specific functional locations are actin filament, muscle thin filament tropomyosin, cytoskeleton, and, where directly supported, stress-fiber/cytoskeletal structures. Supporting Evidence: file:human/TPM3/TPM3-uniprot.txt Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction |
| GO:0005829 cytosol | TAS Reactome:R-HSA-390597 | KEEP AS NON CORE | Summary: This cytosol annotation derives from a Reactome muscle contraction pathway step. It is compatible with TPM3-containing thin-filament complexes but is less informative than actin filament, muscle thin filament tropomyosin, or cytoskeleton localization. Reason: Keep cytosol as non-core pathway context because TPM3 is a cytoskeletal/thin-filament actin-binding protein. The specific functional locations are actin filament, muscle thin filament tropomyosin, cytoskeleton, and, where directly supported, stress-fiber/cytoskeletal structures. Supporting Evidence: file:human/TPM3/TPM3-uniprot.txt Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction |
| GO:0005829 cytosol | TAS Reactome:R-HSA-390598 | KEEP AS NON CORE | Summary: This cytosol annotation derives from a Reactome muscle contraction pathway step. It is compatible with TPM3-containing thin-filament complexes but is less informative than actin filament, muscle thin filament tropomyosin, or cytoskeleton localization. Reason: Keep cytosol as non-core pathway context because TPM3 is a cytoskeletal/thin-filament actin-binding protein. The specific functional locations are actin filament, muscle thin filament tropomyosin, cytoskeleton, and, where directly supported, stress-fiber/cytoskeletal structures. Supporting Evidence: file:human/TPM3/TPM3-uniprot.txt Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction |
| GO:0005829 cytosol | TAS Reactome:R-HSA-445699 | KEEP AS NON CORE | Summary: This cytosol annotation derives from a Reactome muscle contraction pathway step. It is compatible with TPM3-containing thin-filament complexes but is less informative than actin filament, muscle thin filament tropomyosin, or cytoskeleton localization. Reason: Keep cytosol as non-core pathway context because TPM3 is a cytoskeletal/thin-filament actin-binding protein. The specific functional locations are actin filament, muscle thin filament tropomyosin, cytoskeleton, and, where directly supported, stress-fiber/cytoskeletal structures. Supporting Evidence: file:human/TPM3/TPM3-uniprot.txt Smooth muscle contraction is regulated by interaction with caldesmon |
| GO:0005829 cytosol | TAS Reactome:R-HSA-445700 | KEEP AS NON CORE | Summary: This cytosol annotation derives from a Reactome muscle contraction pathway step. It is compatible with TPM3-containing thin-filament complexes but is less informative than actin filament, muscle thin filament tropomyosin, or cytoskeleton localization. Reason: Keep cytosol as non-core pathway context because TPM3 is a cytoskeletal/thin-filament actin-binding protein. The specific functional locations are actin filament, muscle thin filament tropomyosin, cytoskeleton, and, where directly supported, stress-fiber/cytoskeletal structures. Supporting Evidence: file:human/TPM3/TPM3-uniprot.txt Smooth muscle contraction is regulated by interaction with caldesmon |
| GO:0005829 cytosol | TAS Reactome:R-HSA-445704 | KEEP AS NON CORE | Summary: This cytosol annotation derives from a Reactome muscle contraction pathway step. It is compatible with TPM3-containing thin-filament complexes but is less informative than actin filament, muscle thin filament tropomyosin, or cytoskeleton localization. Reason: Keep cytosol as non-core pathway context because TPM3 is a cytoskeletal/thin-filament actin-binding protein. The specific functional locations are actin filament, muscle thin filament tropomyosin, cytoskeleton, and, where directly supported, stress-fiber/cytoskeletal structures. Supporting Evidence: file:human/TPM3/TPM3-uniprot.txt Smooth muscle contraction is regulated by interaction with caldesmon |
| GO:0005829 cytosol | TAS Reactome:R-HSA-445705 | KEEP AS NON CORE | Summary: This cytosol annotation derives from a Reactome muscle contraction pathway step. It is compatible with TPM3-containing thin-filament complexes but is less informative than actin filament, muscle thin filament tropomyosin, or cytoskeleton localization. Reason: Keep cytosol as non-core pathway context because TPM3 is a cytoskeletal/thin-filament actin-binding protein. The specific functional locations are actin filament, muscle thin filament tropomyosin, cytoskeleton, and, where directly supported, stress-fiber/cytoskeletal structures. Supporting Evidence: file:human/TPM3/TPM3-uniprot.txt Smooth muscle contraction is regulated by interaction with caldesmon |
| GO:0001725 stress fiber | IDA PMID:16236705 h2-Calponin is regulated by mechanical tension and modifies ... | UNDECIDED | Summary: Stress fiber localization is plausible for non-muscle cytoskeletal TPM3 isoforms, but the cached PMID:16236705 abstract supports h2-calponin effects on actin cytoskeleton rather than direct TPM3 stress-fiber localization. Reason: The available cached evidence does not directly establish TPM3 localization to stress fibers. This annotation should remain undecided unless the full text or GO source confirms that TPM3 itself was assayed in stress fibers, or a direct TPM3 localization source is added. Supporting Evidence: PMID:16236705 Force-expression of h2-calponin enhanced the resistance of the actin filaments to cytochalasin B treatment file:human/TPM3/TPM3-uniprot.txt In non-muscle cells is implicated in stabilizing cytoskeleton actin filaments |
| GO:0005856 cytoskeleton | TAS PMID:16130169 Proteomics of human umbilical vein endothelial cells applied... | ACCEPT | Summary: This TAS annotation for cytoskeleton localization derives from PMID:16130169, a proteomics study of HUVECs during etoposide-induced apoptosis. The study identified tropomyosin among proteins varying during apoptosis, indicating cytoskeletal involvement. The study confirmed "cellular functions more related to cell motility" among identified proteins. Reason: The cytoskeleton annotation is correct for TPM3, which is established as a cytoskeletal protein. UniProt lists "Cytoplasm, cytoskeleton" as the subcellular location. While more specific terms (actin filament, stress fiber) exist, this general term is acceptable. Supporting Evidence: PMID:16130169 illustrates various cellular functions more related to cell motility and angiogenesis file:human/TPM3/TPM3-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton |
| GO:0005856 cytoskeleton | NAS PMID:3418707 Organization of the hTMnm gene. Implications for the evoluti... | ACCEPT | Summary: This NAS annotation for cytoskeleton derives from PMID:3418707, the foundational paper on hTMnm gene organization. The study characterized the gene producing both muscle and non-muscle (cytoskeletal) tropomyosin isoforms, clearly establishing TPM3's role in cytoskeletal function. The paper describes "TM30nm, a 248 amino acid cytoskeletal tropomyosin" in non-muscle cells. Reason: This annotation directly refers to TPM3's cytoskeletal function as established in the original characterization of the gene. The paper explicitly describes the cytoskeletal isoform TM30nm. This is a core localization for the non-muscle isoforms of TPM3. Supporting Evidence: PMID:3418707 In non-muscle tissue this gene produces a 2.5 kb (1 kb = 10(3) bases or base-pairs) mRNA encoding TM30nm, a 248 amino acid cytoskeletal tropomyosin |
| GO:0005862 muscle thin filament tropomyosin | TAS PMID:3018581 Tissue-specific expression of the human tropomyosin gene inv... | KEEP AS NON CORE | Summary: This TAS annotation for muscle thin filament tropomyosin derives from PMID:3018581, which characterized the tissue-specific expression of the TPM3 gene. The paper describes that in skeletal muscle, the gene produces "a 1.3-kb mRNA encoding a 285-amino-acid tropomyosin" which functions as part of the muscle thin filament. Reason: This annotation is accurate for the skeletal muscle isoform (Isoform 1, 285 AA) but not for the cytoskeletal isoforms. The muscle thin filament tropomyosin complex is specific to muscle tissue where TPM3 Isoform 1 functions with the troponin complex for calcium-regulated contraction. Since this is isoform-specific, it represents a non-core localization. The core localization applicable to all isoforms is "actin filament" (GO:0005884). Supporting Evidence: PMID:3018581 a 1.3-kb mRNA encoding a 285-amino-acid tropomyosin in human skeletal muscle file:human/TPM3/TPM3-uniprot.txt Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction file:human/TPM3/TPM3-deep-research-falcon.md Falcon report emphasizes TPM3 actin-filament binding/stabilization, isoform-specific actin filament identity, and thin-filament regulation in muscle. |
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Download this section (compressed HTML)Q: Which TPM3 isoforms should receive isoform-specific GO annotation for muscle contraction versus non-muscle actin cytoskeleton organization?
Suggested experts: GO isoform annotation curators, muscle biologists
Q: Which high-throughput TPM3 protein-binding annotations correspond to functional actin/thin-filament biology rather than nonspecific interactome detections?
Suggested experts: protein interaction curators, cytoskeleton specialists
Experiment: Compare major TPM3 isoforms for F-actin binding, filament stabilization, myosin regulation, and protection from cofilin/gelsolin-mediated disassembly.
Hypothesis: Distinct TPM3 isoforms specify actin filament populations with different mechanical and regulatory properties.
Type: Isoform-specific actin filament assay
Experiment: Use long-read transcriptomics and targeted proteomics in slow skeletal muscle and non-muscle cells to map TPM3 isoform expression to GO-relevant functions.
Hypothesis: Muscle contraction annotations map mainly to skeletal muscle isoform 1, whereas cytoskeletal organization annotations map to shorter non-muscle isoforms.
Type: Endogenous isoform mapping
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