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Tropomyosin Edit Wikipedia article
- 1 Myosin and the actin skeleton
- 2 Isoforms and evolution
- 3 Genes and isoforms (isoform complexity)
- 4 Splicing
- 5 Evolution of isoform generation
- 6 Spatial sorting of tropomyosin isoforms
- 7 Isoforms are not functionally redundant
- 8 Specific roles and functions
- 9 Role in diseases
- 10 Tools and technologies to study tropomyosins
- 11 References
- 12 External links
Myosin and the actin skeleton
All organisms contain structures that provide physical integrity to their cells. These structures are collectively known as the cytoskeleton, and one of the most ancient systems is based on filamentous polymers of the protein actin. A second polymer of the protein, tropomyosin, is an integral part of most actin filaments in animals.
Tropomyosins are a large family of integral components of actin filaments that play a critical role in regulating the function of actin filaments in both muscle and nonmuscle cells. These proteins consist of rod-shaped coiled-coil hetero- or homo-dimers that lie along the α-helical groove of most actin filaments. Interaction occurs along the length of the actin filament, with dimers aligning in a head-to-tail fashion.
Tropomyosins are often categorised into two groups, muscle tropomyosin isoforms and nonmuscle tropomyosin isoforms. Muscle tropomyosin isoforms are involved in regulating interactions between actin and myosin in the muscle sarcomere and play a pivotal role in regulated muscle contraction. Nonmuscle tropomyosin isoforms function in all cells, both muscle and nonmuscle cells, and are involved in a range of cellular pathways that control and regulate the cell's cytoskeleton and other key cellular functions.
The actin filament system that is involved in regulating these cellular pathways is more complex than the actin filament systems that regulates muscle contraction. The contractile system relies upon 4 actin filament isoforms and 5 tropomyosin isoforms, whereas the actin filament system of the cytoskeleton uses two actin filament isoforms and over 40 tropomyosin isoforms.
Isoforms and evolution
In direct contrast of the 'one gene, one polypeptide' rule, we now know from a combination of genomic sequencing, such as the Human Genome Project and EST data of expressed proteins that many eukaryotes produce a range of proteins from a single gene. This plays a crucial role in the functionality of higher eukaryotes, with humans expressing more than 5 times as many different proteins (isoforms) through alternative splicing than they have genes. From a mechanistic point of view, it is much easier for an organism to expand on a current gene/protein family (creating protein isoforms) than it is to create an entirely new gene. From an evolutionary point of view, tropomyosins in higher eukaryotes are notable in retaining all 4 of the potential genes produced by the dual genomic duplication event that took place in early eukaryotic evolution. 
Genes and isoforms (isoform complexity)
Within mammals, four genes are responsible for generating more than 40 different tropomyosin isoforms. In terms of structure, the genes are very similar, suggesting that they arose through gene duplication of an ancestral gene. In humans, these genes are no longer linked and are widely dispersed. In humans, the α-, β-, γ-, and δ-genes are formally known as TPM1, TPM2, TPM3, and TPM4 and are located at 15q22, 9p13, 1q22 and 19p13, respectively.
Isoforms are defined as highly related gene products that perform, in essence, similar biological functions, with variations existing between the isoforms in terms of biological activity, regulatory properties, temporal and spatial expression, and/or the intercellular location. Isoforms are produced by two distinct mechanisms, gene duplication and alternative splicing. The former mechanism is a process by which multiple copies of a gene are generated through unequal crossing over, through tandem duplication, or by translocation. Alternative splicing is a mechanism wherein exons are either retained in the mRNA or targeted for removal in different combinations to create a diverse array of mRNAs from a single pre-mRNA.
A vast array of tropomyosin isoforms are generated by using a combination of different genes and alternative splicing. In mammals, regardless of the gene, transcription is initiated at the start of either exon 1a or exon 1b. Depending on which promoter and initial exon used, the tropomyosin isoforms can be categorized as either high-molecular-weight (HMW, 284 amino acids) or low-molecular-weight (LMW, 248). HMW isoforms express exon 1a and either 2a or 2b, while LMW isoforms express exon 1b. To date, all known tropomyosins contain exons 3-9. Alternative splicing can occur at exon 6, with the mutually exclusive choice of exon 6a or 6b. At the c-terminus, the transcript is spliced again at exon 9, with the choice of exon 9a, 9b, 9c, or 9d.
Evolution of isoform generation
In terms of structure, the genes are very similar, suggesting that they arose through gene duplication of an ancestral gene. The most highly related genes are the α- and γ-genes, utilizing two promoters and differing only with the presence of the unique 2a exon in the α-gene. Although substantial differences between alternative exons from the same gene have been revealed by sequence comparison (1a and 1b, 6a and 6b, and the exon 9s), most exons are, however, highly conserved between the different genes. For example, exon 1a and 1b from the α-gene vary considerably in sequence; however, the sequence from exon 1a from the α-, β-, γ-, and δ-genes is highly conserved.
Due to the conservative nature of the genes, it is believed that the genes evolved from a common ancestral gene, giving rise to over 40 functionally distinct isoforms. The expression of these isoforms is highly regulated and variable throughout development. The diversity of tropomyosin expression, both in space and in time, provides the potential not only to regulate actin filament function but to create specialised actin filament populations.
Spatial sorting of tropomyosin isoforms
Numerous reports detail that tropomyosin isoforms are sorted to different intracellular locations, often associating with actin filament populations that are involved in specific processes. Direct visualization of spatial segregation of isoforms was initially observed by Burgoyne and Norman and soon after by Lin and co-workers. They observed that specific isoforms were associated with distinct cellular structures. Using specific antibodies, they were able to identify the presence of both HMW and the LMW isoforms of the γ-gene in stress fibers; however, only LMW isoforms were detected in ruffling membranes.
These studies have been extended to a number of cell types with similar results. Extensive studies in neuronal cells, fibroblasts, skeletal muscle and osteoclast cells has further highlighted the complex association tropomyosin isoforms have with cellular structures. These studies have led to the realization that the regulation of isoform sorting is extremely complex and highly regulated.
Regulation of sorting
Sorting of tropomyosin isoforms in discrete intracellular locations is developmentally regulated. Initial studies reported that the sorting of isoforms changed through development, where Tropomyosin 4 was initially localized to the growth cone of growing neurons, but in mature neurons it was relocated to the somatodendritic compartment. These observations have been supported by studies on different tropomyosin isoforms, showing how tropomyosin populations were relocated during neuron maturation. This evidence is supportive of the notion that tropomyosin isoforms are subject to temporal regulation.
Additional studies have identified the role the cell cycle plays in isoform sorting. A study that screened a range HMW products from the α- and β-genes and compared localisation with LMW products from the γ-gene found that the HMW and LMW products are mutually exclusively segregated during the early G1 phase of the cell cycle.
Mechanism of sorting
While studies suggest that tropomyosin sorting may be influenced by the sorting of mRNAs, there is no absolute correlation between mRNA and protein location. In neurons, Tropomyosin 5NM1 mRNA was found to sort to the pole of the neuron elaborating an axon prior to morphological differentiation. The sorting of Tropomyosin 5NM1/2 mRNA to this location correlated with the expression of the Tropomyosin 5NM1/2 protein. In contrast, the mRNA encoding the Tropomyosin Br2 protein was excluded from the pole of the neuron.
The link between mRNA sorting and protein location has been tested in transgenic mice models. The models were created so that the coding regions of Tropomyosin 5NM1/2 and Tropomyosin 3 were expressed under the control of the β-actin promoter with the a β-actin 3'-untranslated region lacking targeting information. The study found that Tropomyosin 3, an isoform that is not normally expressed in neuronal cells, was broadly distributed throughout the neuron, while exogenous expression of the neuronal isoform Tropomyosin 5NM1/2 was found to sort to the growth cone of neurons as does the endogenous Tropomyosin 5NM1/2. As these two transgenes differ only in the tropomyosin coding region yet are localized in two distinct areas, the findings suggest that, in addition to mRNA sorting, the proteins themselves contain sorting information.
Studies suggest that tropomyosin isoform sorting may also be influenced by the actin isoform composition of microfilaments. In myoblasts, overexpression of γ-actin resulted in the down-regulation of β–actin and the removal of Tropomyosin 2 but not Tropomyosin 5 from stress fibers. It was later found that, when cells were exposed to cytochalasin D, a chemical that results in the disorganization of actin filaments, tropomyosin isoform sorting was disrupted. Upon the washing out of cytochalasin D, tropomyosin isoform sorting was re-established. This is suggestive of a strong relationship between the process of tropomyosin isoform sorting and the incorporation of tropomyosin isoforms into organized arrays of actin filaments. There is no evidence for active transport of tropomyosin isoforms to specific locations. Rather, it appears that sorting is the result of local assembly of preferred isoforms at specific intracellular site. The mechanisms that underlie tropomyosin isoform sorting appear to be inherently flexible and dynamic in nature.
Isoforms are not functionally redundant
Many studies have led to the understanding that tropomyosins perform essential functions and are required in a diverse range of species from yeast, worms, and flies to complex mammals.
The essential role of tropomyosins was discovered in the Bretscher laboratory, where researchers found that, by eliminating the TPM1 gene of budding yeasts, growth rates were reduced, the presence of actin cables disappeared, defects in vesicular transport were observed, and mating of the yeast was poor. When a second yeast gene, TPM2, was deleted, no observable changes in the phenotype were recorded; however, when deleted in combination with TPM1, it resulted in lethality. This suggests that TPM1 and -2 genes have overlapping function; however, TPM2 cannot fully compensate of the loss of TPM1, indicating that some functions of TPM1 are unique. Similar results have been observed in flies, worms, amphibians, and mammals, confirming previous results and suggestive of tropomyosin's being involved in a wide range of cellular functions. However, the three co-expressed TMP1, 2, and 4 genes cannot compensate for deletion of the TPM3 gene in embryonic stem cells and preimplantation mouse embryos.
Results from gene knockout experiments can be ambiguous and must be carefully examined. In studies in which the deletion of a gene leads to lethality, it can at first appear that the gene product had a truly unique role. However, lethality can also be the result of the inability of the compromised cell to express other isoforms to rescue the phenotype because the required isoform is not naturally expressed in the cell.
Specific roles and functions
Influencing binding of actin binding proteins to actin filaments
The actin microfilament system is the fundamental cytoskeletal system involved in the development and maintenance of cell morphology. The ability of this system to readily respond to cellular cues and undergo structural re-organisation has led to the belief that this system regulates specific structural changes within different cellular regions.
Within humans, there are only six actin isoforms, and these isoforms are responsible for an array of unique and complex cellular structures and key cellular interactions. It is thought that the function and form of the actin cytoskeleton is controlled largely by actin-binding proteins (ABP) that are associated with the actin polymer. ABP are a group of proteins that bind to actin. Although tropomyosin is sometimes included as an ABP, it is not a true ABP. The tropomyosin dimer has very low affinity for an actin filament and forms no van der waals contacts with actin. It is only the formation of a tropomyosin polymer's winding around the actin filament that provides stability to the tropomyosin-actin filament interaction.
Many studies suggest that the binding of tropomyosin isoforms to an actin filament may influence the binding of other ABPs, which together alter the structure and convey specific properties and ultimately specific functions to an actin filament. This is demonstrated in neuroepithelial cells, where increased expression of Tropomyosin 5NM1 increases the recruitment of myosin IIB, a myosin motor protein to the growth cone area. However, the over-expression of Tropomyosin Br3 had the opposite effect, decreasing myosin activity in the same region.
In a pioneering study by Bernstein and Bamburg, it was observed that the actin-binding protein actin depolymerisation factor (ADF)/cofilin, a factor that promotes actin filament depolymerisation, competed with tropomyosin for binding to the actin filament. The expression of Tropomyosin 5NM1 in neuronal cells eliminated ADF/cofilin from the growth cone region, leading to more stable actin filaments. However, the increased expression of Tropomyosin Br3 was observed to recruit ADF/cofilin to actin filaments bound to the Tropomyosin Br3 isoform within the lamellipodium, which led to the disassembly of actin filaments. This phenomenon, whereby a specific tropomyosin isoform directs specific interactions between actin-binding proteins, and the actin filament has been observed in a variety of model systems with a range of different binding proteins (reviewed in Gunning et al., 2008). These interactions, under the influence of tropomyosin isoforms, allow actin filaments to be involved in a diverse range of cellular functions.
Function in skeletal muscle contraction
Skeletal muscle is composed of large, multi-nucleated cells (muscle fibers). Each muscle fiber is packed with longitudinal arrays of myofibrils. Myofibrils are composed of repeating protein structures or sarcomeres, the basic functional unit of skeletal muscle. The sarcomere is a highly structured protein array, consisting of interdigitating thick and thin filaments, where the thin filaments are tethered to a protein structure, the Z-line. The dynamic interaction between the thick and thin filaments results in muscle contraction.
Myosin belongs to a family of motor proteins, and the muscle isoforms of this family comprise the thick filament. The thin filament is made of the skeletal muscle isoforms of actin. Each myosin protein 'paddles' along the thin actin filament, repeatedly binding to myosin-binding sites along the actin filament, ratcheting and letting go. In effect, the thick filament moves or slides along the thin filament, resulting in muscle contraction. This process is known as the sliding filament model.
The binding of the myosin heads to the muscle actin is a highly regulated process. The thin filament is made of actin, tropomyosin, and troponin. The contraction of skeletal muscle is triggered by nerve impulses that in turn stimulate the release of Ca2+. The release of Ca2+ from the sarcoplasmic reticulum causes an increase in the concentration of Ca2+ in the cytosol. Calcium ions then bind to troponin, which is associated with tropomyosin. Binding causes changes in the shape of troponin and subsequently causes the tropomyosin isoform to shift its position on the actin filament. This shifting in position exposes the myosin-binding sites on the actin filament, allowing the myosin heads of the thick filament to bind to the thin filament.
Structural and biochemical studies suggest that the position of tropomyosin and troponin on the thin filament regulates the interactions between the myosin heads of the thick filament and the binding sites on the actin of the thin filament. X-ray diffraction and cryoelectron microscopy suggest that tropomyosin sterically blocks the access of myosin to the actin filament.
Although this model is well-established, it is unclear as to whether the movement of tropomyosin directly causes the myosin head to engage the actin filament. As such, an alternative model has emerged, whereby the movement of the tropomyosin in the filament functions as an allosteric switch that is modulated by activating myosin binding but does not function solely by regulating myosin binding.
Regulation of contraction in smooth muscle
Smooth muscle is a type of non-striated muscle, and, unlike striated muscle, contraction of smooth muscle is not under conscious control. Smooth muscle may contract spontaneously or rhythmically and be induced by a number of physiochemical agents (hormones, drugs, neurotransmitters). Smooth muscle is found within the walls of various organs and tubes in the body such as the esophagus, stomach, intestines, bronchi, urethra, bladder, and blood vessels.
Although smooth muscles do not form regular arrays of thick and thin filaments like the sarcomeres of striated muscles, contraction is still due to the same sliding filament mechanism controlled by myosin crossbridges interacting with actin filaments. The thin filament of smooth muscle is made of actin, tropomyosin, caldesmon, and calmodulin. Within this type of muscle, caldesmon and calmodulin control the tropomyosin-mediated transition between on and off activity states. Caldesmon binds to actin, tropomyosin, calmodulin, and myosin, of which its interactions with actin are most important. The binding of caldesmon is strongly influenced by tropomyosin. Caldesmon is an inhibitor of actinomyosin ATPase and motility, and both actin binding and caldesmon inhibition are greatly enhanced in the presence of tropomyosin.
Smooth muscle contraction is initiated by the release of Ca2+. Ca2+ binds to and activates calmodulin, which then binds to caldesmon. This binding causes the caldesmon protein to disengage from the actin filament, exposing the myosin-binding sites on the actin filament. Myosin motor heads are phosphorylated by myosin light-chain kinase, allowing the myosin head to interact with the actin filament and cause contraction.
Role in cytoskeleton function
The cytoskeleton is an elaborate network of filaments required for the proper functioning of a range of cellular processes including cell motility, cell division, intracellular trafficking, and the maintenance of cell shape. The cytoskeleton is composed of three distinct filament systems: microtubules, intermediate filaments, and microfilaments (also known as the actin cytoskeleton). It is the dynamic interactions between these filaments that provide cells with unique structures and functions.
A number of regulatory mechanisms, employing many actin-binding proteins, have evolved to control the dynamics of the actin filament system. It is believed that tropomyosins play a pivotal role in this regulatory system, influencing the associations the actin filament has with other ABPs. Together, these associations confer specific properties on the filament, allowing these structures to be involved in a wide range of cellular processes, but also to rapidly respond to cellular stimuli.
Role in diseases
Many studies have shown that there are specific changes to the repertoire of tropomyosins expressed in cells that are undergoing cellular transformation. These highly reproducible results suggest that, during the process of cellular transformation, a process whereby a normal cell becomes malignant, there is a decreased synthesis of HMW tropomyosin isoforms. In the initial studies, transformation of rat embryo fibroblast cell line REF-52 and of normal rat kidney cells led to decreased synthesis of HMW tropomyosins. In both of these systems, the down regulation was contributed to a decrease in the mRNA levels. These early results suggested that tropomyosins played a critical role in facilitating certain processes that occurred during cell transformation, such as actin filament re-organisation and changes in cell shape. These studies have been reproduced in other laboratories and in other cell lines, with similar results (reviewed in Gunning et al., 2008).
Furthermore, studies have highlighted a link between tropomyosin isoform expression and the acquisition of metastatic properties. A study compared isoform expression between a low- and highly-metastatic Lewis lung carcinoma cell line. It is interesting to note that the study found that, as cells become more metastatic, there is a marked decrease in the expression of HMW tropomyosin 2 protein and mRNA levels.
These results have been confirmed in primary tumors and human models. Studies in colon and bladder cancer found increased expression of the LMW tropomyosin Tropomyosin 5NM1. The elevated expression of this isoform has also been seen in transformed rat fibroblasts, and it is thought that this isoform is required for the motility of highly metastatic melanoma. In addition, elevated expression of Tropomyosin 4 has been linked with lymph node metastasis in breast cancer.
All of these studies suggest that changes in the expression and complement of tropomyosin isoforms are integral to cancer and cancer progression. The consensus is that, in general, cancer cells become more reliant on LMW tropomyosins as HMW tropomyosins disappear with increasing malignancy. This discovery has led to the development of novel anti-tropomyosin compounds as potential anti-cancer agents.
Tropomyosins have been implicated in the autoimmune disease ulcerative colitis, a disease of the colon that is characterised by ulcers or open sores. The link between this disease and tropomyosin was first acknowledged in a study that found blood serum taken from 95% of patients with ulcerative colitis contained antibodies that reacted positively to tropomyosin. Additional studies have confirmed these results, but also identify Tropomyosin 5 and Tropomyosin 1 as the primary tropomyosins involved in the pathogenesis of ulcerative colitis. Tropomyosin 5 has been related to the development of pouchitis in the ileal pouch following surgery for ulcerative colitis. The elevated number of IgG-producing cells in the colonic mucosa of ulcerative colitis patients is largely committed to producing IgG against Tropomyosin 5-related epitopes. Tropomyosin 5 is, therefore, capable of inducing a significant T-cell response. A physicochemical analysis of common structural motifs present in 109 human autoantigens revealed that tropomyosins have the highest number of such motifs, and thus a very high propensity to act as autoantigens.
In addition to the role tropomyosins play in ulcerative colitis, tropomyosin antibodies have also been reported in acute rheumatic fever and the inflammatory disorder Behcet's syndrome. In both instances, it is unclear as to whether these antibodies play a direct role in the pathogenesis of these human conditions or reflect the high antigenicity of tropomyosins released from compromised cells.
Nemaline myopathy is a muscle disease that is characterised by the presence of electron-dense rod bodies in skeletal muscle fibers. These electron-dense rod bodies are composed mainly of α-actinin and actin. The disorder is often clinically categorized into several groups, including mild (typical), intermediate, severe, and adult-onset; however, these distinctions are somewhat ambiguous, as the categories frequently overlap. Causative mutations have been detected in skeletal α-actinin, tropomyosin, nebulin, and troponin. Within humans, mutations in both the γ-Tropomyosin and β-Tropomyosin genes have been identified. No mutations in the α-Tropomyosin gene have been identified in this condition for humans.
Tools and technologies to study tropomyosins
Within the scientific community, there is great interest in tropomyosin isoforms, and, given the vast array of processes that this protein has been reported to be involved with, it is not surprising.
One way in which this protein and, what is more important, specific isoforms can be studied in detail is through the use of antibodies. These specific antibodies can be used in protein-blotting experiments and applied to cells or tissue sections and observed under a microscope. This allows researchers not only to determine the level or concentration of an isoform or a group of isoforms but also to identify the cellular location of a particular isoform and associations with other cellular structures or proteins.
At the present time, there are many commercially available antibodies; however, many of these antibodies are sold with minimal information regarding the antigen used to raise the antibody and, therefore, the isoform specificity, as such some research groups develop their own antibodies. Before these antibodies can be used, they must be extensively characterised, a process whereby the specificity of the antibody is examined to ensure that the antibody does not cross-react with other tropomyosins or other proteins.
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- Hannan, AJ; Gunning, P; Jeffrey, PL; Weinberger, RP; Weinberger, RP (1995). "Intracellular localization of tropomyosin mRNA and protein is associated with development of neuronal polarity". Mol Cell Neurosci. 6 (5): 397–412. PMID 8581312. doi:10.1006/mcne.1995.1030.
- Schevzov, G; Bryce, NS; Almonte-Baldonado, R; Joya, J; Lin, JJ; Hardeman, E; Weinberger, R; Gunning, P (2005). "Specific features of neuronal size and shape are regulated by tropomyosin isoforms". Mol Biol Cell. 16 (7): 3425–3437. PMC . PMID 15888546. doi:10.1091/mbc.E04-10-0951.
- Schevzov, G; Lloyd, C; Hailstones, D; Gunning, P (1993). "Differential regulation of tropomyosin isoform organization and gene expression in response to altered actin gene expression". J Cell Biol. 121 (4): 811–821. PMC . PMID 8491774. doi:10.1083/jcb.121.4.811.
- Schevzov, G; Gunning, P; Jeffrey, PL; Temm-Grove, C; Helfman, DM; Lin, JJ; Weinberger, RP (1997). "Tropomyosin localization reveals distinct populations of microfilaments in neurites and growth cones". Mol Cell Neurosci. 8 (6): 439–454. PMID 9143561. doi:10.1006/mcne.1997.0599.
- Lui, H; Bretscher, A (1992). "Characterization of TPM1 disrupted yeast cells indicates an involvement of tropomyosin in directed vesicular transport". J Cell Biol. 118 (2): 285–299. PMC . PMID 1629236. doi:10.1083/jcb.118.2.285.
- Bryce, NS; Schevzov, G; Ferguson, V; Percival, JM; Lin, JJ; Matsumura, F; Bamburg, JR; Jeffrey, PL; et al. (2003). "Specification of actin filament function and molecular composition by tropomyosin isoform". Mol Biol Cell. 14 (3): 1002–1016. PMC . PMID 12631719. doi:10.1091/mbc.E02-04-0244.
- Bernstein, BW; Bamburg, JR (1982). "Tropomyosin binding to F-actin protects the F-actin from disassembly by brain actin-depolymerizing factor (ADF)". Cell Motil. 2 (1): 1–8. PMID 6890875. doi:10.1002/cm.970020102.
- Hendricks, M; Weintraub, H (1981). "Tropomyosin is decreased in transformed cells". Proc Natl Acad Sci USA. 78 (9): 5633–5637. Bibcode:1981PNAS...78.5633H. PMC . PMID 6272310. doi:10.1073/pnas.78.9.5633.
- Hendricks, M; Weintraub, H (1984). "Multiple tropomyosin polypeptides in chicken embryo fibroblasts: differential repression of transcription by Rous sarcoma virus transformation". Mol Cell Biol. 4 (9): 1823–1833. PMC . PMID 6208481. doi:10.1128/MCB.4.9.1823.
- Lin, JJ; Helfman, DM; Hughes, SH; Chou, CS (1985). "Tropomyosin isoforms in chicken embryo fibroblasts: purification, characterization, changes in Rous sarcoma virus-transformed cells". J Cell Biol. 100 (3): 692–703. PMC . PMID 2982883. doi:10.1083/jcb.100.3.692.
- Takenaga, K; Nakamura, Y; Sakiyama, S (1988). "Differential expression of a tropomyosin isoform in low- and high-metastatic Lewis lung carcinoma cells". Mol Cell Biol. 8 (9): 3934–3937. PMC . PMID 3221870.
- Takenaga, K; Nakamura, Y; Tokunaga, K; Kageyama, H; Sakiyama, S (1988). "Isolation and characterization of a cDNA that encodes mouse fibroblast tropomyosin isoform2". Mol Cell Biol. 8 (12): 5561–5565. PMC . PMID 3244365.
- Lin, JL; Geng, X; Bhattacharya, SD; Yu, JR; Reiter, RS; Sastri, B; Glazier, KD; Mirza, ZK; et al. (2002). "Isolation and sequencing of a novel tropomyosin isoform preferentially associated with colon cancer". Gastroenterology. 123 (1): 152–162. PMID 12105844. doi:10.1053/gast.2002.34154.
- Pawlak, G; McGarvey, TW; Nguyen, TB; Tomaszewski, JE; Puthiyaveettil, R; Malkowicz, SB; Helfman, DM (2004). "Alterations in tropomyosin isoform expression in human transitional cell carcinoma of the urinary bladder". Int J Cancer. 110 (3): 368–373. PMID 15095301. doi:10.1002/ijc.20151.
- Miyado, K; Kimura, M; Taniguchi, S (1996). "Decreased expression of a single tropomyosin isoform, TM5/TM30nm, results in reduction in motility of highly metastatic B16-F10 mouse melanome cells". Biochem Biophys Res Commun. 225 (2): 427–435. PMID 8753779. doi:10.1006/bbrc.1996.1190.
- Das, KM; Dasgupta, A; Mandal, A; Geng, X (1993). "Autoimmunity to cytoskeletal protein tropomyosin. A clue to the pathogenetic mechanism fr ulcerative colitis". J Immunol. 150 (6): 2487–2493. PMID 8450225.
- biancone, L; Monteleone, G; Marasco, R; Pallone, F (1998). "Autoimmunity to tropomyosinisoforms in ulcerative colitis (UC) patients and unaffected relatives". Clin Exp Immunol. 113 (2): 198–205. PMC . PMID 9717968. doi:10.1046/j.1365-2249.1998.00610.x.
- Geng, X; Biancone, L; Dai, HH; Lin, JJ; Yoshizaki, N; Dasgupta, A; Pallone, F; Das, KM (1998). "Tropomyosin isoform in intestinal mucosa: production of autoantibodies to tropomyosin isoform in ulcerative colitis". Gastroenterology. 114 (5): 912–922. PMID 9558279. doi:10.1016/S0016-5085(98)70310-5.
- Biancone, L; Palmieri, G; Lombardi, A; Colantoni, A; Tonelli, F; Das, KM; Pallone, F (2003). "tropomyosin expression in the ileal pouch: a relationship with the development of pouchitis in ulcerative colitis". Am J Gastroenterol. 98 (12): 2719–2726. PMID 14687823. doi:10.1111/j.1572-0241.2003.08719.x.
- Dohlam, JG; Lupas, A; Carson, M (1993). "Long charge-rich alpha-helices in systemic autoantigens". Biochem Biophys Res Commun. 195 (2): 686–696. PMID 8373407. doi:10.1006/bbrc.1993.2100.
- Khanna, AK; Nomura, Y; Fischetti, VA; Zabriskie, JB (1997). "Antibodies in the sera of acute rheumatic fever patients bind to human cardiac tropomyosin". J Autoimmunity. 10: 99–106. doi:10.1006/jaut.1996.0107.
- Mor, F; Weinberger, A; Cohen, IR (2002). "Identification of alpha-tropomyosin as a target self-antigen in Behcet's syndrome". Eur J Immunol. 32 (2): 356–365. PMID 11807775. doi:10.1002/1521-4141(200202)32:2<356::AID-IMMU356>3.0.CO;2-9.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Tropomyosin Provide feedback
Tropomyosin is an alpha-helical protein that forms a coiled-coil structure of 2 parallel helices containing 2 sets of 7 alternating actin binding sites . The protein is best known for its role in regulating the interaction between actin and myosin in muscle contraction, but is also involved in the organisation and dynamics of the cytoskeleton in non-muscle cells . There are multiple cell-specific isoforms, expressed by alternative promoters and alternative RNA processing of at least four genes . Muscle isoforms of tropomyosin are characterised by having 284 amino acid residues and a highly conserved N-terminal region, whereas non-muscle forms are generally smaller and are heterogeneous in their N-terminal region .
Internal database links
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR000533
Tropomyosins [PUBMED:3606587], are a family of closely related proteins present in muscle and non-muscle cells. In striated muscle, tropomyosin mediate the interactions between the troponin complex and actin so as to regulate muscle contraction [PUBMED:12690456]. The role of tropomyosin in smooth muscle and non-muscle tissues is not clear. Tropomyosin is an alpha-helical protein that forms a coiled-coil structure of 2 parallel helices containing 2 sets of 7 alternating actin binding sites [PUBMED:6993480]. There are multiple cell-specific isoforms, created by differential splicing of the messenger RNA from one gene, but the proportions of the isoforms vary between different cell types. Muscle isoforms of tropomyosin are characterised by having 284 amino acid residues and a highly conserved N-terminal region, whereas non-muscle forms are generally smaller and are heterogeneous in their N-terminal region.
This entry represents tropomyosin (Tmp) 1, 2 and 3. Within the yeast Tmp1 and Tmp2, biochemical and sequence analyses indicate that Tpm2 spans four actin monomers along a filament, whereas Tpm1 spans five. Despite its shorter length, Tpm2 can compete with Tpm1 for binding to F-actin. Over-expression of Tpm2 in vivo alters the axial budding of haploids to a bipolar pattern, and this can be partially suppressed by co-over-expression of Tpm1. This suggests distinct functions for the two tropomyosins, and indicates that the ratio between them is important for correct morphogenesis [PUBMED:7844152].
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
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We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the UniProtKB sequence database using the family HMM
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
If you find these logos useful in your own work, please consider citing the following article:
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Author:||Finn RD, Richardson L|
|Number in seed:||21|
|Number in full:||1366|
|Average length of the domain:||187.30 aa|
|Average identity of full alignment:||50 %|
|Average coverage of the sequence by the domain:||72.97 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||19|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There are 7 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Tropomyosin domain has been found. There are 80 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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