TPM2

TPM2
Identifiers
Aliases TPM2, AMCD1, DA1, DA2B, HEL-S-273, NEM4, TMSB, tropomyosin 2 (beta)
External IDs HomoloGene: 134045 GeneCards: TPM2
RNA expression pattern


More reference expression data
Orthologs
Species Human Mouse
Entrez

7169

n/a

Ensembl

ENSG00000198467

n/a

UniProt

P07951

n/a

RefSeq (mRNA)

NM_001145822
NM_001301226
NM_001301227
NM_003289
NM_213674

n/a

RefSeq (protein)

NP_003280.2
NP_998839.1

n/a

Location (UCSC) Chr 9: 35.68 – 35.69 Mb n/a
PubMed search [1] n/a
Wikidata
View/Edit Human

β-Tropomyosin, also known as tropomyosin beta chain is a protein that in humans is encoded by the TPM2 gene.[2][3] β-tropomyosin is striated muscle-specific coiled coil dimer that functions to stabilize actin filaments and regulate muscle contraction.

Structure

β-tropomyosin is roughly 32 kDa in molecular weight (284 amino acids), but multiple splice variants exist.[4][5][6][7] Tropomysin is a flexible protein homodimer or heterodimer composed of two alpha-helical chains, which adopt a bent coiled coil conformation to wrap around the seven actin molecules in a functional unit of muscle. It is polymerized end to end along the two grooves of actin filaments and provides stability to the filaments.[8] Tropomyosin dimers are composed of varying combinations of tropomyosin isoforms; human striated muscles express protein from the TPM1 (α-tropoomyosin), TPM2 (β-tropomyosin) and TPM3 (γ-tropomyosin) genes, with α-tropomyosin being the predominant isoform in striated muscle. Fast skeletal muscle and cardiac muscle contain more αα-homodimers, and slow skeletal muscle contains more ββ-homodimers.[9] In human cardiac muscle the ratio of α-tropomyosin to β-tropomyosin is roughly 5:1.[10][11] It has been shown that different combinations of tropomyosin isoforms bind troponin T with differing affinities, demonstrating that isoform combinations are used to impart a specific functional impact.[9]

Function

β-tropomyosin functions in association with α-tropomyosin and the troponin complex—composed of troponin I, troponin C and troponin T—to modulated the actin and myosin interaction. In diastole, the tropomyosin-troponin complex inhibits this interaction, and during systole the rise in intracellular calcium from sarcoplasmic reticulum binds to troponin C and induces a conformational change in the troponin-tropomyosin complex that disinhibits the actomyosin ATPase and permits contraction.[9]

Specific functional insights into the function of the β-tropomyosin isoform have come from studies employing transgenesis. A study overexpressing β-tropomyosin in adult cardiac muscle evoked a 34-fold increase in expression of β-tropomyosin, resulting in preferential formation of the αβ-tropomyosin heterodimer. Transgenic hearts showed a significant delay in relaxation time as well as a decrease in the maximum rate of left ventricular relaxation.[9] A more aggressive overexpression of β-tropomyosin (to over 75% of total tropomyosin) in the heart causes death of mice 10–14 days old, along with cardiac abnormalities, suggesting that the normal distribution of tropomyosin isoforms is critical to normal cardiac function.[12]

In a disease model of cardiac hypertrophy, β-tropomyosin was shown to be reexpressed within two days following induction of pressure overload.[13]

Studies from mice, which express 98% α-tropomyosin, have shown that α-tropomyosin can be phosphorylated at Serine-283, which is one amino acid away from the C-terminus. β-tropomyosin also has a Serine residue at position 283,[14] thus, it is likely that β-tropomyosin is also phosphorylated. Mouse transgenic studies in which the phosphorylation site in α-tropomyosin is mutated to Alanine have shown that phosphorylation may function to modulate tropomyosin polymerization, head-to-tail interactions between adjacent tropomyosin molecules, cooperativity, myosin ATPase activity, and the cardiac response to stress.[15]

Clinical significance

A decrease in β-tropomyosin in patients with heart failure was demonstrated, as failing ventricles expressed solely α-tropomyosin.[16]

Heterozygous mutations in TPM2 have been identified in patients with congenital cap myopathy, a rare disorder defined by cap-like structures in muscle fiber periphery.[17][18][19][20]

Mutations in TPM2 have also been associated with nemaline myopathy, a rare disorder characterized by muscle weakness and nemaline bodies,[21][22][23]

as well as distal arthrogryposis.[24][25]

The muscle weakness observed in these patients may be due to a change in mutated TPM2 affinity for actin or decreased calcium-induced activation of contractility.[26][27][28] Moreover, studies unveiled alterations in cross-bridge attachment and detachment rates,[29] as well as changes in ATPase rates.[27][30]

Interactions

TPM2 has been shown to interact with:

References

  1. ↑ "Human PubMed Reference:".
  2. ↑ Hunt CC, Eyre HJ, Akkari PA, Meredith C, Dorosz SM, Wilton SD, Callen DF, Laing NG, Baker E (Aug 1995). "Assignment of the human beta tropomyosin gene (TPM2) to band 9p13 by fluorescence in situ hybridisation". Cytogenetics and Cell Genetics. 71 (1): 94–5. doi:10.1159/000134070. PMID 7606936.
  3. ↑ "Entrez Gene: TPM2 tropomyosin 2 (beta)".
  4. ↑ Perry SV (2001). "Vertebrate tropomyosin: distribution, properties and function". Journal of Muscle Research and Cell Motility. 22 (1): 5–49. doi:10.1023/A:1010303732441. PMID 11563548.
  5. ↑ "Protein sequence of human TPM2 (Uniprot ID: P07951)". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Retrieved 1 July 2015.
  6. ↑ "Protein sequence of human TPM2 (Uniprot ID: P07951-2)". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Retrieved 1 July 2015.
  7. ↑ "Protein sequence of human TPM2 (Uniprot ID: P07951-3)". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Retrieved 1 July 2015.
  8. ↑ Brown JH, Kim KH, Jun G, Greenfield NJ, Dominguez R, Volkmann N, Hitchcock-DeGregori SE, Cohen C (Jul 2001). "Deciphering the design of the tropomyosin molecule". Proceedings of the National Academy of Sciences of the United States of America. 98 (15): 8496–501. doi:10.1073/pnas.131219198. PMC 37464Freely accessible. PMID 11438684.
  9. 1 2 3 4 Muthuchamy M, Grupp IL, Grupp G, O'Toole BA, Kier AB, Boivin GP, Neumann J, Wieczorek DF (Dec 1995). "Molecular and physiological effects of overexpressing striated muscle beta-tropomyosin in the adult murine heart". The Journal of Biological Chemistry. 270 (51): 30593–603. doi:10.1074/jbc.270.51.30593. PMID 8530495.
  10. ↑ Dube DK, McLean MD, Dube S, Poiesz BJ (Sep 2014). "Translational control of tropomyosin expression in vertebrate hearts". Anatomical Record. 297 (9): 1585–95. doi:10.1002/ar.22978. PMID 25125172.
  11. ↑ Yin Z, Ren J, Guo W (Jan 2015). "Sarcomeric protein isoform transitions in cardiac muscle: a journey to heart failure". Biochimica et Biophysica Acta. 1852 (1): 47–52. doi:10.1016/j.bbadis.2014.11.003. PMC 4268308Freely accessible. PMID 25446994.
  12. ↑ Muthuchamy M, Boivin GP, Grupp IL, Wieczorek DF (Aug 1998). "Beta-tropomyosin overexpression induces severe cardiac abnormalities". Journal of Molecular and Cellular Cardiology. 30 (8): 1545–57. doi:10.1006/jmcc.1998.0720. PMID 9737941.
  13. ↑ Izumo S, Nadal-Ginard B, Mahdavi V (Jan 1988). "Protooncogene induction and reprogramming of cardiac gene expression produced by pressure overload". Proceedings of the National Academy of Sciences of the United States of America. 85 (2): 339–43. doi:10.1073/pnas.85.2.339. PMID 2963328.
  14. ↑ "Protein sequence alignment of human TPM1 and TPM2". Uniprot Knowledgebase. Retrieved 2 July 2015.
  15. ↑ Schulz, EM; Wieczorek, DF (August 2013). "Tropomyosin de-phosphorylation in the heart: what are the consequences?". Journal of muscle research and cell motility. 34 (3-4): 239–46. doi:10.1007/s10974-013-9348-7. PMID 23793376.
  16. ↑ Purcell IF, Bing W, Marston SB (Sep 1999). "Functional analysis of human cardiac troponin by the in vitro motility assay: comparison of adult, foetal and failing hearts". Cardiovascular Research. 43 (4): 884–91. doi:10.1016/s0008-6363(99)00123-6. PMID 10615415.
  17. ↑ Ohlsson M, Quijano-Roy S, Darin N, Brochier G, Lacène E, Avila-Smirnow D, Fardeau M, Oldfors A, Tajsharghi H (Dec 2008). "New morphologic and genetic findings in cap disease associated with beta-tropomyosin (TPM2) mutations". Neurology. 71 (23): 1896–901. doi:10.1212/01.wnl.0000336654.44814.b8. PMID 19047562.
  18. ↑ Tajsharghi H, Ohlsson M, Lindberg C, Oldfors A (Sep 2007). "Congenital myopathy with nemaline rods and cap structures caused by a mutation in the beta-tropomyosin gene (TPM2)". Archives of Neurology. 64 (9): 1334–8. doi:10.1001/archneur.64.9.1334. PMID 17846275.
  19. ↑ Lehtokari VL, Ceuterick-de Groote C, de Jonghe P, Marttila M, Laing NG, Pelin K, Wallgren-Pettersson C (Jun 2007). "Cap disease caused by heterozygous deletion of the beta-tropomyosin gene TPM2". Neuromuscular Disorders. 17 (6): 433–42. doi:10.1016/j.nmd.2007.02.015. PMID 17434307.
  20. ↑ Clarke NF, Domazetovska A, Waddell L, Kornberg A, McLean C, North KN (May 2009). "Cap disease due to mutation of the beta-tropomyosin gene (TPM2)". Neuromuscular Disorders. 19 (5): 348–51. doi:10.1016/j.nmd.2009.03.003. PMID 19345583.
  21. ↑ Mokbel N, Ilkovski B, Kreissl M, Memo M, Jeffries CM, Marttila M, Lehtokari VL, Lemola E, Grönholm M, Yang N, Menard D, Marcorelles P, Echaniz-Laguna A, Reimann J, Vainzof M, Monnier N, Ravenscroft G, McNamara E, Nowak KJ, Laing NG, Wallgren-Pettersson C, Trewhella J, Marston S, Ottenheijm C, North KN, Clarke NF (Feb 2013). "K7del is a common TPM2 gene mutation associated with nemaline myopathy and raised myofibre calcium sensitivity". Brain. 136 (Pt 2): 494–507. doi:10.1093/brain/aws348. PMID 23378224.
  22. ↑ Monnier N, Lunardi J, Marty I, Mezin P, Labarre-Vila A, Dieterich K, Jouk PS (Feb 2009). "Absence of beta-tropomyosin is a new cause of Escobar syndrome associated with nemaline myopathy". Neuromuscular Disorders. 19 (2): 118–23. doi:10.1016/j.nmd.2008.11.009. PMID 19155175.
  23. ↑ Donner K, Ollikainen M, Ridanpää M, Christen HJ, Goebel HH, de Visser M, Pelin K, Wallgren-Pettersson C (Feb 2002). "Mutations in the beta-tropomyosin (TPM2) gene--a rare cause of nemaline myopathy". Neuromuscular Disorders. 12 (2): 151–8. doi:10.1016/s0960-8966(01)00252-8. PMID 11738357.
  24. ↑ Tajsharghi H, Kimber E, Holmgren D, Tulinius M, Oldfors A (Mar 2007). "Distal arthrogryposis and muscle weakness associated with a beta-tropomyosin mutation". Neurology. 68 (10): 772–5. doi:10.1212/01.wnl.0000256339.40667.fb. PMID 17339586.
  25. ↑ Sung SS, Brassington AM, Grannatt K, Rutherford A, Whitby FG, Krakowiak PA, Jorde LB, Carey JC, Bamshad M (Mar 2003). "Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes". American Journal of Human Genetics. 72 (3): 681–90. doi:10.1086/368294. PMC 1180243Freely accessible. PMID 12592607.
  26. ↑ Marttila M, Lehtokari VL, Marston S, Nyman TA, Barnerias C, Beggs AH, Bertini E, Ceyhan-Birsoy O, Cintas P, Gerard M, Gilbert-Dussardier B, Hogue JS, Longman C, Eymard B, Frydman M, Kang PB, Klinge L, Kolski H, Lochmüller H, Magy L, Manel V, Mayer M, Mercuri E, North KN, Peudenier-Robert S, Pihko H, Probst FJ, Reisin R, Stewart W, Taratuto AL, de Visser M, Wilichowski E, Winer J, Nowak K, Laing NG, Winder TL, Monnier N, Clarke NF, Pelin K, Grönholm M, Wallgren-Pettersson C (Jul 2014). "Mutation update and genotype-phenotype correlations of novel and previously described mutations in TPM2 and TPM3 causing congenital myopathies". Human Mutation. 35 (7): 779–90. doi:10.1002/humu.22554. PMID 24692096.
  27. 1 2 Robinson P, Lipscomb S, Preston LC, Altin E, Watkins H, Ashley CC, Redwood CS (Mar 2007). "Mutations in fast skeletal troponin I, troponin T, and beta-tropomyosin that cause distal arthrogryposis all increase contractile function". FASEB Journal. 21 (3): 896–905. doi:10.1096/fj.06-6899com. PMID 17194691.
  28. ↑ Marttila M, Lemola E, Wallefeld W, Memo M, Donner K, Laing NG, Marston S, Grönholm M, Wallgren-Pettersson C (Feb 2012). "Abnormal actin binding of aberrant β-tropomyosins is a molecular cause of muscle weakness in TPM2-related nemaline and cap myopathy". The Biochemical Journal. 442 (1): 231–9. doi:10.1042/BJ20111030. PMID 22084935.
  29. ↑ Ochala J, Li M, Tajsharghi H, Kimber E, Tulinius M, Oldfors A, Larsson L (Jun 2007). "Effects of a R133W beta-tropomyosin mutation on regulation of muscle contraction in single human muscle fibres". The Journal of Physiology. 581 (Pt 3): 1283–92. doi:10.1113/jphysiol.2007.129759. PMID 17430991.
  30. ↑ Marston S, Memo M, Messer A, Papadaki M, Nowak K, McNamara E, Ong R, El-Mezgueldi M, Li X, Lehman W (Dec 2013). "Mutations in repeating structural motifs of tropomyosin cause gain of function in skeletal muscle myopathy patients". Human Molecular Genetics. 22 (24): 4978–87. doi:10.1093/hmg/ddt345. PMID 23886664.
  31. ↑ Zhu J, Bilan PJ, Moyers JS, Antonetti DA, Kahn CR (Jan 1996). "Rad, a novel Ras-related GTPase, interacts with skeletal muscle beta-tropomyosin". The Journal of Biological Chemistry. 271 (2): 768–73. doi:10.1074/jbc.271.2.768. PMID 8557685.
  32. ↑ Guy PM, Kenny DA, Gill GN (Jun 1999). "The PDZ domain of the LIM protein enigma binds to beta-tropomyosin". Molecular Biology of the Cell. 10 (6): 1973–84. doi:10.1091/mbc.10.6.1973. PMC 25398Freely accessible. PMID 10359609.
  33. ↑ Brown HR, Schachat FH (Apr 1985). "Renaturation of skeletal muscle tropomyosin: implications for in vivo assembly". Proceedings of the National Academy of Sciences of the United States of America. 82 (8): 2359–63. doi:10.1073/pnas.82.8.2359. PMC 397557Freely accessible. PMID 3857586.

Further reading

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