TPM3

Existing Annotations Review

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 UniProt:P06753 Binds to actin filaments in muscle and non-muscle cells
GO:0007015 actin filament organization	IBA GO_REF:0000033	ACCEPT	Summary: TPM3 contributes to actin filament organization in both muscle and non-muscle contexts. In non-muscle cells, UniProt states TPM3 "is implicated in stabilizing cytoskeleton actin filaments" [UniProt P06753]. PMID:16236705 demonstrated TPM3 localization to stress fibers and its role in cytoskeletal organization. The muscle isoform also contributes to thin filament organization. This process annotation appropriately captures the functional 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: UniProt:P06753 In non-muscle cells is implicated in stabilizing cytoskeleton actin filaments PMID:16236705 epidermal keratinocytes and fibroblast cells express significant amounts of h2-calponin [studied alongside tropomyosin in stress fiber context]
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: UniProt:P06753 Binds to actin filaments in muscle and non-muscle cells
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: UniProt:P06753 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
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: UniProt:P06753 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: UniProt:P06753 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 UniProt:P06753 Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction
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 [large-scale interactome study]
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 [large-scale Y2H study]
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 [high-throughput interactome study]
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 [high-throughput study]
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 [large-scale interactome study]
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 [high-throughput interactome study]
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 [high-throughput screening method]
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-κB 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: UniProt:P06753 SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton
GO:0005515 protein binding	IPI PMID:35510366 Autosomal dominantly inherited myopathy likely caused by the...	ACCEPT	Summary: This IPI annotation from PMID:35510366 documents TPM3 interaction with TNNT1 (slow skeletal troponin T1). The study showed "complex formation of TnT1-D65A with tropomyosin 3 (TPM3) was enhanced" and that wild-type TnT1 interacts with TPM3 via co-immunoprecipitation. This is a functionally relevant interaction in the muscle thin filament complex, but is annotated with the generic "protein binding" term. Reason: While "protein binding" is generally uninformative, this specific annotation documents a functionally relevant interaction between TPM3 and TNNT1 in the muscle thin filament complex. The interaction is important for understanding TPM3's role in muscle contraction regulation. UniProt confirms "Interacts with TNNT1" [UniProt P06753]. This annotation is acceptable as it documents a characterized binary interaction, though a more specific term would be preferred. Supporting Evidence: PMID:35510366 complex formation of TnT1-D65A with tropomyosin 3 (TPM3) was enhanced UniProt:P06753 Interacts with TNNT1
GO:0005829 cytosol	TAS Reactome:R-HSA-9700179	ACCEPT	Summary: This TAS annotation derives from Reactome pathway R-HSA-9700179 (Ligand-independent dimerization of ALK fusions), which documents TPM3-ALK fusion proteins in cancer. The annotation indicates cytosolic localization for the TPM3-ALK fusion protein. While this relates to an oncogenic fusion, cytosol is still an appropriate localization for TPM3-containing proteins. Reason: Cytosol is an appropriate general localization for TPM3, which functions as a cytoskeletal protein. While this Reactome entry relates to TPM3-ALK fusion proteins in cancer, the cytosolic localization is consistent with TPM3's normal distribution in the cytoplasm where it associates with actin filaments. Accepting for consistency with other cytosol annotations. Supporting Evidence: Reactome:R-HSA-9700179 In addition to NPM, fusions with ALK have also been identified with EML4 UniProt:P06753 SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton
GO:0005829 cytosol	TAS Reactome:R-HSA-9700181	ACCEPT	Summary: This TAS annotation derives from Reactome pathway R-HSA-9700181 (Autophosphorylation of ALK fusions), which documents TPM3-ALK fusion protein signaling in cancer. The annotation indicates cytosolic localization consistent with TPM3's normal cytoplasmic distribution. Reason: Cytosol is an appropriate general localization for TPM3. While this Reactome entry relates to TPM3-ALK fusion proteins, the cytosolic localization is consistent with TPM3's normal distribution in the cytoplasm. Accepting for consistency with other cytosol annotations. Supporting Evidence: Reactome:R-HSA-9700181 After partner protein-mediated dimerization, ALK fusions are trans-autophosphorylated by the ALK kinase domain UniProt:P06753 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	ACCEPT	Summary: This TAS annotation derives from Reactome pathway R-HSA-390593 (ATP Hydrolysis By Myosin), which is part of the striated muscle contraction pathway. TPM3 participates as part of the thin filament regulatory complex. The cytosol annotation is generic but appropriate for the muscle sarcomere context where the muscle contraction machinery operates. Reason: The cytosol annotation reflects the location of the muscle contraction machinery where TPM3 functions as part of the thin filament. While "muscle thin filament" would be more specific, the cytosol term is acceptable for the Reactome pathway context. This applies to the muscle isoform (Isoform 1). 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	ACCEPT	Summary: This TAS annotation derives from Reactome pathway R-HSA-390595 (Calcium Binds Troponin-C), part of striated muscle contraction. TPM3 works in concert with the troponin complex for calcium-dependent regulation of muscle contraction. Reason: The cytosol annotation reflects the location of TPM3 in the muscle contraction machinery. TPM3 functions with the troponin complex in calcium-dependent muscle contraction regulation. This applies to the muscle isoform (Isoform 1). Supporting Evidence: UniProt:P06753 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	ACCEPT	Summary: This TAS annotation derives from Reactome pathway R-HSA-390597 (Release Of ADP From Myosin), part of striated muscle contraction. TPM3 is part of the thin filament regulatory machinery in this pathway. Reason: The cytosol annotation reflects the location of the muscle contraction machinery. This is a duplicate cytosol annotation from a related Reactome muscle contraction pathway step. Valid for the muscle isoform context. Supporting Evidence: UniProt:P06753 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	ACCEPT	Summary: This TAS annotation derives from Reactome pathway R-HSA-390598 (Myosin Binds ATP), part of striated muscle contraction. TPM3 participates in the thin filament regulatory complex in this pathway. Reason: The cytosol annotation reflects the location of the muscle contraction machinery. Duplicate cytosol annotation from Reactome muscle contraction pathway. Valid for muscle isoform context. Supporting Evidence: UniProt:P06753 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	ACCEPT	Summary: This TAS annotation derives from Reactome pathway R-HSA-445699 (ATP Hydrolysis By Myosin), part of smooth muscle contraction. TPM3 participates in smooth muscle through interaction with caldesmon for regulation as noted in UniProt. Reason: The cytosol annotation reflects the location of muscle contraction machinery. This relates to smooth muscle contraction where TPM3 interacts with caldesmon for regulation. Valid for smooth muscle context. Supporting Evidence: UniProt:P06753 Smooth muscle contraction is regulated by interaction with caldesmon
GO:0005829 cytosol	TAS Reactome:R-HSA-445700	ACCEPT	Summary: This TAS annotation derives from Reactome pathway R-HSA-445700 (Myosin Binds ATP), part of smooth muscle contraction pathway. Reason: The cytosol annotation reflects the location of muscle contraction machinery. Duplicate from Reactome smooth muscle contraction pathway. Supporting Evidence: UniProt:P06753 Smooth muscle contraction is regulated by interaction with caldesmon
GO:0005829 cytosol	TAS Reactome:R-HSA-445704	ACCEPT	Summary: This TAS annotation derives from Reactome pathway R-HSA-445704 (Calcium Binds Caldesmon), part of smooth muscle contraction pathway where TPM3 participates in caldesmon-regulated contraction. Reason: The cytosol annotation reflects the location of muscle contraction machinery. This relates to smooth muscle contraction regulation via caldesmon. Supporting Evidence: UniProt:P06753 Smooth muscle contraction is regulated by interaction with caldesmon
GO:0005829 cytosol	TAS Reactome:R-HSA-445705	ACCEPT	Summary: This TAS annotation derives from Reactome pathway R-HSA-445705 (Release Of ADP From Myosin), part of smooth muscle contraction pathway. Reason: The cytosol annotation reflects the location of muscle contraction machinery. Duplicate from Reactome smooth muscle contraction pathway. Supporting Evidence: UniProt:P06753 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 ...	ACCEPT	Summary: This IDA annotation for stress fiber localization derives from PMID:16236705, which studied h2-calponin regulation by mechanical tension. The study examined tropomyosin alongside calponin in the context of actin cytoskeleton and stress fibers. Stress fibers are contractile actin bundles in non-muscle cells where cytoskeletal tropomyosins (like TPM3 isoform 2/TM30nm) localize. Reason: Stress fiber localization is appropriate for the cytoskeletal isoforms of TPM3 (especially Isoform 2/TM30nm). Non-muscle tropomyosins associate with stress fibers to help stabilize these contractile actin structures. This represents a core localization for cytoskeletal TPM3 isoforms, complementing the muscle thin filament localization for muscle isoforms. Supporting Evidence: PMID:16236705 Force-expression of h2-calponin enhanced the resistance of the actin filaments to cytochalasin B treatment UniProt:P06753 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 UniProt:P06753 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 UniProt:P06753 Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction

Isoform	UniProt ID	Synonym	Tissue	Key Feature
Isoform 1	P06753-1	Skeletal muscle	Slow skeletal muscle	Type I fibers
Isoform 2	P06753-2	TM30nm, Cytoskeletal	Non-muscle cells	30nm variant

📄 View Raw YAML

id: P06753
gene_symbol: TPM3
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: '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.'
existing_annotations:
- term:
    id: GO:0051015
    label: actin filament binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:3018581
      supporting_text: 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
    - reference_id: UniProt:P06753
      supporting_text: Binds to actin filaments in muscle and non-muscle cells
- term:
    id: GO:0007015
    label: actin filament organization
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: TPM3 contributes to actin filament organization in both muscle and non-muscle
      contexts. In non-muscle cells, UniProt states TPM3 "is implicated in stabilizing
      cytoskeleton actin filaments" [UniProt P06753]. PMID:16236705 demonstrated TPM3
      localization to stress fibers and its role in cytoskeletal organization. The
      muscle isoform also contributes to thin filament organization. This process
      annotation appropriately captures the functional role of tropomyosins in organizing
      actin filament architecture.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: UniProt:P06753
      supporting_text: In non-muscle cells is implicated in stabilizing cytoskeleton
        actin filaments
    - reference_id: PMID:16236705
      supporting_text: epidermal keratinocytes and fibroblast cells express significant
        amounts of h2-calponin [studied alongside tropomyosin in stress fiber context]
- term:
    id: GO:0005884
    label: actin filament
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: UniProt:P06753
      supporting_text: Binds to actin filaments in muscle and non-muscle cells
- term:
    id: GO:0006936
    label: muscle contraction
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: UniProt:P06753
      supporting_text: Plays a central role, in association with the troponin complex,
        in the calcium dependent regulation of vertebrate striated muscle contraction
    - reference_id: PMID:3018581
      supporting_text: a 1.3-kb mRNA encoding a 285-amino-acid tropomyosin in human
        skeletal muscle
- term:
    id: GO:0003779
    label: actin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    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).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: UniProt:P06753
      supporting_text: Binds to actin filaments in muscle and non-muscle cells
- term:
    id: GO:0005856
    label: cytoskeleton
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: UniProt:P06753
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton'
- term:
    id: GO:0005862
    label: muscle thin filament tropomyosin
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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.
    action: KEEP_AS_NON_CORE
    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).
    supported_by:
    - reference_id: PMID:3418707
      supporting_text: 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
    - reference_id: UniProt:P06753
      supporting_text: Plays a central role, in association with the troponin complex,
        in the calcium dependent regulation of vertebrate striated muscle contraction
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14743216
  review:
    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].
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:14743216
      supporting_text: A physical and functional map of the human TNF-alpha/NF-kappa
        B signal transduction pathway [large-scale interactome study]
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:16189514
      supporting_text: Towards a proteome-scale map of the human protein-protein interaction
        network [large-scale Y2H study]
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17353931
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:17353931
      supporting_text: Large-scale mapping of human protein-protein interactions by
        mass spectrometry [high-throughput interactome study]
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21516116
  review:
    summary: This annotation from PMID:21516116 (next-generation sequencing for interactome
      datasets) uses the generic "protein binding" term from high-throughput interaction
      data.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:21516116
      supporting_text: Next-generation sequencing to generate interactome datasets
        [high-throughput study]
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: A proteome-scale map of the human interactome network [large-scale
        interactome study]
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25910212
  review:
    summary: This annotation from PMID:25910212 (macromolecular interaction perturbations
      in genetic disorders) uses the generic "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:25910212
      supporting_text: Widespread macromolecular interaction perturbations in human
        genetic disorders [interaction perturbation study]
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25959826
  review:
    summary: This annotation from PMID:25959826 (interaction proteomics of neurodegenerative
      disease proteins) uses the generic "protein binding" term from high-throughput
      interaction data.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:25959826
      supporting_text: Quantitative interaction proteomics of neurodegenerative disease
        proteins [high-throughput interactome study]
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27107012
  review:
    summary: This annotation from PMID:27107012 (Barcode Fusion Genetics pooled-matrix
      protein interaction screens) uses the generic "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:27107012
      supporting_text: Pooled-matrix protein interaction screens using Barcode Fusion
        Genetics [high-throughput screening method]
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29128334
  review:
    summary: This annotation from PMID:29128334 (mitochondrial protein interactions
      linked to neurodegeneration) uses the generic "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:29128334
      supporting_text: A Map of Human Mitochondrial Protein Interactions Linked to
        Neurodegeneration Reveals New Mechanisms of Redox Homeostasis and NF-κB Signaling
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  review:
    summary: This annotation from PMID:31515488 (disruption of protein interactions
      by genetic variants) uses the generic "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:31515488
      supporting_text: Extensive disruption of protein interactions by genetic variants
        across the allele frequency spectrum in human populations
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: A reference map of the human binary protein interactome
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  review:
    summary: This annotation from PMID:32814053 (interactome mapping of neurodegenerative
      disease proteins) uses the generic "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: Interactome Mapping Provides a Network of Neurodegenerative
        Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: This annotation from PMID:33961781 (dual proteome-scale networks for
      cell-specific interactome remodeling) uses the generic "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: Dual proteome-scale networks reveal cell-specific remodeling
        of the human interactome
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  review:
    summary: This annotation from PMID:40205054 (multimodal cell maps for structural
      and functional genomics) uses the generic "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:40205054
      supporting_text: Multimodal cell maps as a foundation for structural and functional
        genomics
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: UniProt:P06753
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35510366
  review:
    summary: This IPI annotation from PMID:35510366 documents TPM3 interaction with
      TNNT1 (slow skeletal troponin T1). The study showed "complex formation of TnT1-D65A
      with tropomyosin 3 (TPM3) was enhanced" and that wild-type TnT1 interacts with
      TPM3 via co-immunoprecipitation. This is a functionally relevant interaction
      in the muscle thin filament complex, but is annotated with the generic "protein
      binding" term.
    action: ACCEPT
    reason: While "protein binding" is generally uninformative, this specific annotation
      documents a functionally relevant interaction between TPM3 and TNNT1 in the
      muscle thin filament complex. The interaction is important for understanding
      TPM3's role in muscle contraction regulation. UniProt confirms "Interacts with
      TNNT1" [UniProt P06753]. This annotation is acceptable as it documents a characterized
      binary interaction, though a more specific term would be preferred.
    supported_by:
    - reference_id: PMID:35510366
      supporting_text: complex formation of TnT1-D65A with tropomyosin 3 (TPM3) was
        enhanced
    - reference_id: UniProt:P06753
      supporting_text: Interacts with TNNT1
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9700179
  review:
    summary: This TAS annotation derives from Reactome pathway R-HSA-9700179 (Ligand-independent
      dimerization of ALK fusions), which documents TPM3-ALK fusion proteins in cancer.
      The annotation indicates cytosolic localization for the TPM3-ALK fusion protein.
      While this relates to an oncogenic fusion, cytosol is still an appropriate localization
      for TPM3-containing proteins.
    action: ACCEPT
    reason: Cytosol is an appropriate general localization for TPM3, which functions
      as a cytoskeletal protein. While this Reactome entry relates to TPM3-ALK fusion
      proteins in cancer, the cytosolic localization is consistent with TPM3's normal
      distribution in the cytoplasm where it associates with actin filaments. Accepting
      for consistency with other cytosol annotations.
    supported_by:
    - reference_id: Reactome:R-HSA-9700179
      supporting_text: In addition to NPM, fusions with ALK have also been identified
        with EML4
    - reference_id: UniProt:P06753
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9700181
  review:
    summary: This TAS annotation derives from Reactome pathway R-HSA-9700181 (Autophosphorylation
      of ALK fusions), which documents TPM3-ALK fusion protein signaling in cancer.
      The annotation indicates cytosolic localization consistent with TPM3's normal
      cytoplasmic distribution.
    action: ACCEPT
    reason: Cytosol is an appropriate general localization for TPM3. While this Reactome
      entry relates to TPM3-ALK fusion proteins, the cytosolic localization is consistent
      with TPM3's normal distribution in the cytoplasm. Accepting for consistency
      with other cytosol annotations.
    supported_by:
    - reference_id: Reactome:R-HSA-9700181
      supporting_text: After partner protein-mediated dimerization, ALK fusions are
        trans-autophosphorylated by the ALK kinase domain
    - reference_id: UniProt:P06753
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23892143
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:23892143
      supporting_text: Human respiratory syncytial virus N, P and M protein interactions
        in HEK-293T cells
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:20458337
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:20458337
      supporting_text: we first analyzed the total proteome of highly purified B cell-derived
        exosomes using sensitive and accurate mass spectrometry (MS), and identified
        539 proteins
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-390593
  review:
    summary: This TAS annotation derives from Reactome pathway R-HSA-390593 (ATP Hydrolysis
      By Myosin), which is part of the striated muscle contraction pathway. TPM3 participates
      as part of the thin filament regulatory complex. The cytosol annotation is generic
      but appropriate for the muscle sarcomere context where the muscle contraction
      machinery operates.
    action: ACCEPT
    reason: The cytosol annotation reflects the location of the muscle contraction
      machinery where TPM3 functions as part of the thin filament. While "muscle thin
      filament" would be more specific, the cytosol term is acceptable for the Reactome
      pathway context. This applies to the muscle isoform (Isoform 1).
    supported_by:
    - reference_id: Reactome:R-HSA-390593
      supporting_text: The cleft closes like a clam shell around the ATP molecule,
        triggering a large shape change that causes the myosin head to release actin
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-390595
  review:
    summary: This TAS annotation derives from Reactome pathway R-HSA-390595 (Calcium
      Binds Troponin-C), part of striated muscle contraction. TPM3 works in concert
      with the troponin complex for calcium-dependent regulation of muscle contraction.
    action: ACCEPT
    reason: The cytosol annotation reflects the location of TPM3 in the muscle contraction
      machinery. TPM3 functions with the troponin complex in calcium-dependent muscle
      contraction regulation. This applies to the muscle isoform (Isoform 1).
    supported_by:
    - reference_id: UniProt:P06753
      supporting_text: Plays a central role, in association with the troponin complex,
        in the calcium dependent regulation of vertebrate striated muscle contraction
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-390597
  review:
    summary: This TAS annotation derives from Reactome pathway R-HSA-390597 (Release
      Of ADP From Myosin), part of striated muscle contraction. TPM3 is part of the
      thin filament regulatory machinery in this pathway.
    action: ACCEPT
    reason: The cytosol annotation reflects the location of the muscle contraction
      machinery. This is a duplicate cytosol annotation from a related Reactome muscle
      contraction pathway step. Valid for the muscle isoform context.
    supported_by:
    - reference_id: UniProt:P06753
      supporting_text: Plays a central role, in association with the troponin complex,
        in the calcium dependent regulation of vertebrate striated muscle contraction
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-390598
  review:
    summary: This TAS annotation derives from Reactome pathway R-HSA-390598 (Myosin
      Binds ATP), part of striated muscle contraction. TPM3 participates in the thin
      filament regulatory complex in this pathway.
    action: ACCEPT
    reason: The cytosol annotation reflects the location of the muscle contraction
      machinery. Duplicate cytosol annotation from Reactome muscle contraction pathway.
      Valid for muscle isoform context.
    supported_by:
    - reference_id: UniProt:P06753
      supporting_text: Plays a central role, in association with the troponin complex,
        in the calcium dependent regulation of vertebrate striated muscle contraction
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-445699
  review:
    summary: This TAS annotation derives from Reactome pathway R-HSA-445699 (ATP Hydrolysis
      By Myosin), part of smooth muscle contraction. TPM3 participates in smooth muscle
      through interaction with caldesmon for regulation as noted in UniProt.
    action: ACCEPT
    reason: The cytosol annotation reflects the location of muscle contraction machinery.
      This relates to smooth muscle contraction where TPM3 interacts with caldesmon
      for regulation. Valid for smooth muscle context.
    supported_by:
    - reference_id: UniProt:P06753
      supporting_text: Smooth muscle contraction is regulated by interaction with
        caldesmon
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-445700
  review:
    summary: This TAS annotation derives from Reactome pathway R-HSA-445700 (Myosin
      Binds ATP), part of smooth muscle contraction pathway.
    action: ACCEPT
    reason: The cytosol annotation reflects the location of muscle contraction machinery.
      Duplicate from Reactome smooth muscle contraction pathway.
    supported_by:
    - reference_id: UniProt:P06753
      supporting_text: Smooth muscle contraction is regulated by interaction with
        caldesmon
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-445704
  review:
    summary: This TAS annotation derives from Reactome pathway R-HSA-445704 (Calcium
      Binds Caldesmon), part of smooth muscle contraction pathway where TPM3 participates
      in caldesmon-regulated contraction.
    action: ACCEPT
    reason: The cytosol annotation reflects the location of muscle contraction machinery.
      This relates to smooth muscle contraction regulation via caldesmon.
    supported_by:
    - reference_id: UniProt:P06753
      supporting_text: Smooth muscle contraction is regulated by interaction with
        caldesmon
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-445705
  review:
    summary: This TAS annotation derives from Reactome pathway R-HSA-445705 (Release
      Of ADP From Myosin), part of smooth muscle contraction pathway.
    action: ACCEPT
    reason: The cytosol annotation reflects the location of muscle contraction machinery.
      Duplicate from Reactome smooth muscle contraction pathway.
    supported_by:
    - reference_id: UniProt:P06753
      supporting_text: Smooth muscle contraction is regulated by interaction with
        caldesmon
- term:
    id: GO:0001725
    label: stress fiber
  evidence_type: IDA
  original_reference_id: PMID:16236705
  review:
    summary: This IDA annotation for stress fiber localization derives from PMID:16236705,
      which studied h2-calponin regulation by mechanical tension. The study examined
      tropomyosin alongside calponin in the context of actin cytoskeleton and stress
      fibers. Stress fibers are contractile actin bundles in non-muscle cells where
      cytoskeletal tropomyosins (like TPM3 isoform 2/TM30nm) localize.
    action: ACCEPT
    reason: Stress fiber localization is appropriate for the cytoskeletal isoforms
      of TPM3 (especially Isoform 2/TM30nm). Non-muscle tropomyosins associate with
      stress fibers to help stabilize these contractile actin structures. This represents
      a core localization for cytoskeletal TPM3 isoforms, complementing the muscle
      thin filament localization for muscle isoforms.
    supported_by:
    - reference_id: PMID:16236705
      supporting_text: Force-expression of h2-calponin enhanced the resistance of
        the actin filaments to cytochalasin B treatment
    - reference_id: UniProt:P06753
      supporting_text: In non-muscle cells is implicated in stabilizing cytoskeleton
        actin filaments
- term:
    id: GO:0005856
    label: cytoskeleton
  evidence_type: TAS
  original_reference_id: PMID:16130169
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:16130169
      supporting_text: illustrates various cellular functions more related to cell
        motility and angiogenesis
    - reference_id: UniProt:P06753
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton'
- term:
    id: GO:0005856
    label: cytoskeleton
  evidence_type: NAS
  original_reference_id: PMID:3418707
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:3418707
      supporting_text: 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
- term:
    id: GO:0005862
    label: muscle thin filament tropomyosin
  evidence_type: TAS
  original_reference_id: PMID:3018581
  review:
    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.
    action: KEEP_AS_NON_CORE
    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).
    supported_by:
    - reference_id: PMID:3018581
      supporting_text: a 1.3-kb mRNA encoding a 285-amino-acid tropomyosin in human
        skeletal muscle
    - reference_id: UniProt:P06753
      supporting_text: Plays a central role, in association with the troponin complex,
        in the calcium dependent regulation of vertebrate striated muscle contraction
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:14743216
  title: A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction
    pathway.
  findings: []
- id: PMID:16130169
  title: Proteomics of human umbilical vein endothelial cells applied to etoposide-induced
    apoptosis.
  findings: []
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
- id: PMID:16236705
  title: h2-Calponin is regulated by mechanical tension and modifies the function
    of actin cytoskeleton.
  findings: []
- id: PMID:17353931
  title: Large-scale mapping of human protein-protein interactions by mass spectrometry.
  findings: []
- id: PMID:20458337
  title: MHC class II-associated proteins in B-cell exosomes and potential functional
    implications for exosome biogenesis.
  findings: []
- id: PMID:21516116
  title: Next-generation sequencing to generate interactome datasets.
  findings: []
- id: PMID:23892143
  title: Human respiratory syncytial virus N, P and M protein interactions in HEK-293T
    cells.
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:25910212
  title: Widespread macromolecular interaction perturbations in human genetic disorders.
  findings: []
- id: PMID:25959826
  title: Quantitative interaction proteomics of neurodegenerative disease proteins.
  findings: []
- id: PMID:27107012
  title: Pooled-matrix protein interaction screens using Barcode Fusion Genetics.
  findings: []
- id: PMID:29128334
  title: A Map of Human Mitochondrial Protein Interactions Linked to Neurodegeneration
    Reveals New Mechanisms of Redox Homeostasis and NF-κB Signaling.
  findings: []
- id: PMID:3018581
  title: Tissue-specific expression of the human tropomyosin gene involved in the
    generation of the trk oncogene.
  findings: []
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the
    allele frequency spectrum in human populations.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:3418707
  title: Organization of the hTMnm gene. Implications for the evolution of muscle
    and non-muscle tropomyosins.
  findings: []
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
- id: PMID:35510366
  title: Autosomal dominantly inherited myopathy likely caused by the TNNT1 variant
    p.(Asp65Ala).
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: Reactome:R-HSA-390593
  title: ATP Hydrolysis By Myosin
  findings: []
- id: Reactome:R-HSA-390595
  title: Calcium Binds Troponin-C
  findings: []
- id: Reactome:R-HSA-390597
  title: Release Of ADP From Myosin
  findings: []
- id: Reactome:R-HSA-390598
  title: Myosin Binds ATP
  findings: []
- id: Reactome:R-HSA-445699
  title: ATP Hydrolysis By Myosin
  findings: []
- id: Reactome:R-HSA-445700
  title: Myosin Binds ATP
  findings: []
- id: Reactome:R-HSA-445704
  title: Calcium Binds Caldesmon
  findings: []
- id: Reactome:R-HSA-445705
  title: Release Of ADP From Myosin
  findings: []
- id: Reactome:R-HSA-9700179
  title: Ligand-independent dimerization of ALK fusions
  findings: []
- id: Reactome:R-HSA-9700181
  title: Autophosphorylation of ALK fusions
  findings: []
core_functions:
- molecular_function:
    id: GO:0051015
    label: actin filament binding
  description: Actin filament binding is the fundamental molecular function of all
    TPM3 isoforms. Tropomyosins are coiled-coil proteins that bind along the length
    of actin filaments in both muscle and non-muscle cells. UniProt states "Binds
    to actin filaments in muscle and non-muscle cells" [UniProt P06753]. This function
    is conserved across the tropomyosin family (IBA evidence) and is essential for
    TPM3's roles in muscle contraction regulation and cytoskeletal stabilization.
  directly_involved_in:
  - id: GO:0007015
    label: actin filament organization
  locations:
  - id: GO:0005884
    label: actin filament
alternative_products:
- name: 1 (Skeletal muscle)
  id: P06753-1
  description: >-
    The skeletal muscle isoform specific to slow-twitch (type I) muscle fibers. Regulates
    actin-myosin interaction during muscle contraction in slow oxidative fibers. Mutations
    cause nemaline myopathy and congenital fiber type disproportion. GO annotations for
    "muscle contraction" apply to this isoform but NOT to the cytoskeletal isoform 2.
- name: 2 (Cytoskeletal, TM30nm)
  id: P06753-2
  sequence_note: VSP_006604, VSP_006605, VSP_006606
  description: >-
    The cytoskeletal/non-muscle isoform, also called TM30nm or gamma-tropomyosin. Functions
    in non-muscle cells for actin cytoskeleton organization, cell motility, and cytokinesis.
    Has DISTINCT functions from the muscle isoform - GO annotations for "muscle contraction"
    do NOT apply to this isoform.
- name: '3'
  id: P06753-3
  sequence_note: VSP_006604, VSP_006605, VSP_006607
  description: >-
    A cytoskeletal-related isoform. Similar to isoform 2 in having non-muscle functions.
- name: '4'
  id: P06753-4
  sequence_note: VSP_047302, VSP_047303, VSP_047304,
  description: >-
    A less characterized isoform. Functional role not well established in the literature.
- name: '5'
  id: P06753-5
  sequence_note: VSP_047302, VSP_047303, VSP_047304,
  description: >-
    A less characterized isoform. Functional role not well established in the literature.
- name: '6'
  id: P06753-6
  sequence_note: VSP_006604, VSP_006605
  description: >-
    A less characterized isoform. Likely has cytoskeletal functions based on exon usage.
- name: '7'
  id: P06753-7
  sequence_note: VSP_054792, VSP_006606
  description: >-
    A less characterized isoform. Functional role not well established in the literature.

Gene Description

Existing Annotations Review

Core Functions

References

📚 Additional Documentation

Notes

TPM3 (Tropomyosin 3) Notes - ISOFORMS Project

Key Isoform Biology

Tissue-Specific Isoforms

Functional Distinctions

Disease Associations

Relationship to TPM1

Expected Annotation Issues

GOA Annotation Count: 39

📄 View Raw YAML