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Titin, also known as connectin, is the largest known single polypeptide. It is important in the contraction of striated muscle tissues.[1][2] The gene for titin also contains the largest number of introns ever discovered in any single gene.
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Structure
Titin, which consists of 34,350 amino acids, is the largest known protein. The molecular weight of the mature protein is approximately 2,993,442.763 u,[3] and it has a theoretical isoelectric point of 6.01.[4] The protein's empirical chemical formula is C132983H211861N36149O40883S693. It has a theoretical instability index (II) of 39.69, indicating that it would be stable in a test tube. The protein's in vivo half-life, the time it takes for half of the amount of protein in a cell to disappear after its synthesis in the cell, is predicted to be approximately 30 hours (in mammalian reticulocytes).[5]
Titin consists primarily of a linear array of two types of modules (also referred to as protein domains): type I (fibronectin type III domain) and type II (immunoglobulin domain).[6] This linear array is further organized into two regions:
- N-terminal I-band
- acts as the elastic part of the molecule and is composed mainly of type II modules. More specifically the I-band contains two regions of tandem type II immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. Titin is found between the myosin thick filament and the Z disk.[7]
- C-terminal A-band
- is thought to act as a protein-ruler and possesses kinase activity. The A-band is composed of alternating type I and II modules.
Function
Titin is a large abundant protein of striated muscle. A N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere respectively so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Of the many titin variants identified, five for which complete transcript information is available are described.[2][8]
Titin interacts with many sarcomeric proteins including:[9]
- Z line region: telethonin and alpha-actinin
- I band region: calpain-3 and obscurin
- M line region: myosin-binding protein C, calmodulin 1, CAPN3, and MURF1
Clinical relevance
Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9[10][11] and tibial muscular dystrophy.[12] Autoantibodies to titin are produced in patients with the autoimmune disease scleroderma.[13]
Linguistic significance
As the largest known protein, titin also has the longest IUPAC name. The full chemical name, which starts methionyl... and ends ...isoleucine, contains 189,819 letters and is sometimes stated to be the longest word in the English language, or any language.[14] However, professional dictionary writers regard generic names of chemical compounds as verbal formulae rather than English words.[15]
Additional images
 Sliding filament model of muscle contraction. (Titin labeled at upper right.) |
Interactions
Titin has been shown to interact with Telethonin,[16][17][18][19] FHL2,[20] OBSCN,[21] ANK1,[22] ANKRD1,[23] CAPN3,[24][25] ANKRD23[23] and TRIM63.[26]
References
- ^ Online 'Mendelian Inheritance in Man' (OMIM) 188840
- ^ a b "Entrez Gene: TTN titin". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7273.
- ^ Result of Molecular Weight Calculation
- ^ "ExPASy-calculated pI for titin". http://us.expasy.org/cgi-bin/pi_tool1?Q10466@noft@. Retrieved 2007-08-26.
- ^ "Swiss-Prot Protein knowledgebase, main entry". http://us.expasy.org/cgi-bin/niceprot.pl?Q10466. Retrieved 2006-05-04.
- ^ Labeit S, Kolmerer B (October 1995). "Titins: giant proteins in charge of muscle ultrastructure and elasticity". Science 270 (5234): 293–6. PMID 7569978.
- ^ Wang K, McCarter R, Wright J, Beverly J, Ramirez-Mitchell R (August 1991). "Regulation of skeletal muscle stiffness and elasticity by titin isoforms: a test of the segmental extension model of resting tension". Proc. Natl. Acad. Sci. U.S.A. 88 (16): 7101–5. PMID 1714586.
- ^ Labeit S, Barlow DP, Gautel M, Gibson T, Holt J, Hsieh CL, Francke U, Leonard K, Wardale J, Whiting A, Trinick J (May 1990). "A regular pattern of two types of 100-residue motif in the sequence of titin". Nature 345 (6272): 273–6. doi:. PMID 2129545.
- ^ Bang ML, Centner T, Fornoff F, Geach AJ, Gotthardt M, McNabb M, Witt CC, Labeit D, Gregorio CC, Granzier H, Labeit S (November 2001). "The complete gene sequence of titin, expression of an unusual approximately 700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system". Circ. Res. 89 (11): 1065–72. doi:. PMID 11717165. http://circres.ahajournals.org/cgi/pmidlookup?view=long&pmid=11717165.
- ^ Siu BL, Niimura H, Osborne JA, Fatkin D, MacRae C, Solomon S, Benson DW, Seidman JG, Seidman CE (March 1999). "Familial dilated cardiomyopathy locus maps to chromosome 2q31". Circulation 99 (8): 1022–6. PMID 10051295. http://circ.ahajournals.org/cgi/content/abstract/99/8/1022.
- ^ Itoh-Satoh M, Hayashi T, Nishi H, Koga Y, Arimura T, Koyanagi T, Takahashi M, Hohda S, Ueda K, Nouchi T, Hiroe M, Marumo F, Imaizumi T, Yasunami M, Kimura A (February 2002). "Titin mutations as the molecular basis for dilated cardiomyopathy". Biochem. Biophys. Res. Commun. 291 (2): 385–93. doi:. PMID 11846417.
- ^ Hackman P, Vihola A, Haravuori H, Marchand S, Sarparanta J, De Seze J, Labeit S, Witt C, Peltonen L, Richard I, Udd B (September 2002). "Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin". Am. J. Hum. Genet. 71 (3): 492–500. doi:. PMID 12145747.
- ^ Machado C, Sunkel CE, Andrew DJ (April 1998). "Human autoantibodies reveal titin as a chromosomal protein". J. Cell Biol. 141 (2): 321–33. doi:. PMID 9548712.
- ^ "What is the longest word in the English language?". CliffsNotes.com. http://www.cliffsnotes.com/WileyCDA/Section/id-305408,articleId-113603.html. Retrieved 2009-05-26.
- ^ Oxford Word and Language Service team. "Ask the experts - What is the longest English word?". AskOxford.com / Oxford University Press. http://www.askoxford.com/asktheexperts/faq/aboutwords/longestword. Retrieved 2008-01-13.
- ^ Gregorio, C C; Trombitás K, Centner T, Kolmerer B, Stier G, Kunke K, Suzuki K, Obermayr F, Herrmann B, Granzier H, Sorimachi H, Labeit S (Nov. 1998). "The NH2 terminus of titin spans the Z-disc: its interaction with a novel 19-kD ligand (T-cap) is required for sarcomeric integrity". J. Cell Biol. (UNITED STATES) 143 (4): 1013-27. ISSN 0021-9525. PMID 9817758.
- ^ Mayans, O; van der Ven P F, Wilm M, Mues A, Young P, Fürst D O, Wilmanns M, Gautel M (Oct. 1998). "Structural basis for activation of the titin kinase domain during myofibrillogenesis". Nature (ENGLAND) 395 (6705): 863-9. doi:. ISSN 0028-0836. PMID 9804415.
- ^ Zou, Peijian; Gautel Mathias, Geerlof Arie, Wilmanns Matthias, Koch Michel H J, Svergun Dmitri I (Jan. 2003). "Solution scattering suggests cross-linking function of telethonin in the complex with titin". J. Biol. Chem. (United States) 278 (4): 2636-44. doi:. ISSN 0021-9258. PMID 12446666.
- ^ Mues, A; van der Ven P F, Young P, Fürst D O, Gautel M (May. 1998). "Two immunoglobulin-like domains of the Z-disc portion of titin interact in a conformation-dependent way with telethonin". FEBS Lett. (NETHERLANDS) 428 (1-2): 111-4. ISSN 0014-5793. PMID 9645487.
- ^ Lange, Stephan; Auerbach Daniel, McLoughlin Patricia, Perriard Evelyne, Schäfer Beat W, Perriard Jean-Claude, Ehler Elisabeth (Dec. 2002). "Subcellular targeting of metabolic enzymes to titin in heart muscle may be mediated by DRAL/FHL-2". J. Cell. Sci. (England) 115 (Pt 24): 4925-36. ISSN 0021-9533. PMID 12432079.
- ^ Young, P; Ehler E, Gautel M (Jul. 2001). "Obscurin, a giant sarcomeric Rho guanine nucleotide exchange factor protein involved in sarcomere assembly". J. Cell Biol. (United States) 154 (1): 123-36. ISSN 0021-9525. PMID 11448986.
- ^ Kontrogianni-Konstantopoulos, Aikaterini; Bloch Robert J (Feb. 2003). "The hydrophilic domain of small ankyrin-1 interacts with the two N-terminal immunoglobulin domains of titin". J. Biol. Chem. (United States) 278 (6): 3985-91. doi:. ISSN 0021-9258. PMID 12444090.
- ^ a b Miller, Melanie K; Bang Marie-Louise, Witt Christian C, Labeit Dietmar, Trombitas Charles, Watanabe Kaori, Granzier Henk, McElhinny Abigail S, Gregorio Carol C, Labeit Siegfried (Nov. 2003). "The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules". J. Mol. Biol. (England) 333 (5): 951-64. ISSN 0022-2836. PMID 14583192.
- ^ Ono, Y; Shimada H, Sorimachi H, Richard I, Saido T C, Beckmann J S, Ishiura S, Suzuki K (Jul. 1998). "Functional defects of a muscle-specific calpain, p94, caused by mutations associated with limb-girdle muscular dystrophy type 2A". J. Biol. Chem. (UNITED STATES) 273 (27): 17073-8. ISSN 0021-9258. PMID 9642272.
- ^ Sorimachi, H; Kinbara K, Kimura S, Takahashi M, Ishiura S, Sasagawa N, Sorimachi N, Shimada H, Tagawa K, Maruyama K (Dec. 1995). "Muscle-specific calpain, p94, responsible for limb girdle muscular dystrophy type 2A, associates with connectin through IS2, a p94-specific sequence". J. Biol. Chem. (UNITED STATES) 270 (52): 31158-62. ISSN 0021-9258. PMID 8537379.
- ^ Centner, T; Yano J, Kimura E, McElhinny A S, Pelin K, Witt C C, Bang M L, Trombitas K, Granzier H, Gregorio C C, Sorimachi H, Labeit S (Mar. 2001). "Identification of muscle specific ring finger proteins as potential regulators of the titin kinase domain". J. Mol. Biol. (England) 306 (4): 717-26. doi:. ISSN 0022-2836. PMID 11243782.
Further reading
- Kinbara K, Sorimachi H, Ishiura S, Suzuki K (1998). "Skeletal muscle-specific calpain, p49: structure and physiological function". Biochem. Pharmacol. 56 (4): 415–20. PMID 9763216.
- Kolmerer B, Witt CC, Freiburg A, et al. (1999). "The titin cDNA sequence and partial genomic sequences: insights into the molecular genetics, cell biology and physiology of the titin filament system". Rev. Physiol. Biochem. Pharmacol. 138: 19–55. doi:. PMID 10396137.
- Trinick J, Tskhovrebova L (1999). "Titin: a molecular control freak". Trends Cell Biol. 9 (10): 377–80. doi:. PMID 10481174.
- Sorimachi H, Ono Y, Suzuki K (2000). "Skeletal muscle-specific calpain, p94, and connectin/titin: their physiological functions and relationship to limb-girdle muscular dystrophy type 2A". Adv. Exp. Med. Biol. 481: 383–95; discussion 395–7. PMID 10987085.
- Tskhovrebova L, Trinick J (2002). "Role of titin in vertebrate striated muscle". Philos. Trans. R. Soc. Lond., B, Biol. Sci. 357 (1418): 199–206. doi:. PMID 11911777.
- Sela BA (2002). "[Titin: some aspects of the largest protein in the body]". Harefuah 141 (7): 631–5, 665. PMID 12187564.
- Tskhovrebova L, Trinick J (2004). "Properties of titin immunoglobulin and fibronectin-3 domains". J. Biol. Chem. 279 (45): 46351–4. doi:. PMID 15322090.
- Wu Y, Labeit S, Lewinter MM, Granzier H (2003). "Titin: an endosarcomeric protein that modulates myocardial stiffness in DCM". J. Card. Fail. 8 (6 Suppl): S276–86. doi:. PMID 12555133.
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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