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Titin

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Template:PBB Titin, also known as connectin, is a protein that in humans is encoded by the TTN gene.[1][2] Titin is a giant protein that functions as a molecular spring which is responsible for the passive elasticity of muscle. It is composed of 244 individually folded protein domains connected by unstructured peptide sequences.[3] These domains unfold when the protein is stretched and refold when the tension is removed.[4]

Titin is the largest known single polypeptide.[5] Furthermore the gene for titin contains the largest number of exons (363) discovered in any single gene.[6]

Titin is important in the contraction of striated muscle tissues. It connects the Z line to the M line in the sarcomere. The protein contributes to force transmission at the Z line and resting tension in the I band region.[7] It limits the range of motion of the sarcomere in tension, thus contributing to the passive stiffness of muscle. Variations in the sequence of titin between different types of muscle (e.g., cardiac or skeletal) has been correlated with differences in the mechanical properties of these muscles.[1][8]

Isoforms

A number of titin isoforms are produced in different striated muscle tissues as a result of alternative splicing.[9] All but one of these isoforms are in the range of ~27,000 to ~33,000 amino acid residues in length. The exception is the small cardiac novex-3 isoform which is only 5,604 amino acid residues in length. The following table lists the known titin isoforms:

Isoform alias/description length
Q8WZ42-1 the "canonical" full length sequence 34,350
Q8WZ42-3 small cardiac N2-B 26,926
Q8WZ42-4 soleus 33,445
Q8WZ42-6 small cardiac novex-3,
phosphorylated on Thr-5304 and Ser-5306.		 5,604
Q8WZ42-7 cardiac novex-2 27,118
Q8WZ42-8 cardiac novex-1 27,051

Structure

Titin is the largest known protein; its human variant consists of 34,350 amino acids, with the molecular weight of the mature "canonical" isoform of the protein being approximately 3,816,188.13 Da.[10] Its mouse homologue is even larger, comprising 35,213 amino acids with a MW of 3,906,487.6 Da.[11] It has a theoretical isoelectric point of 6.01.[10] The protein's empirical chemical formula is C169 723H270 464N45 688O52 243S912.[10] It has a theoretical instability index (II) of 42.41, classifying the protein as unstable.[10] The protein's in vivo half-life, the time it takes for half of the amount of protein in a cell to break down after its synthesis in the cell, is predicted to be approximately 30 hours (in mammalian reticulocytes).[9]

Titin consists primarily of a linear array of two types of modules (also referred to as protein domains; 244 copies in total): type I (fibronectin type III domain; 132 copies) and type II (immunoglobulin domain; 112 copies).[3] 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.[12]
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 with super-repeat segments. These have been shown to align to the 43 nm axial repeats of myosin thick filaments with immunoglobulin domains correlating to myosin crowns.[13]

Function

Sliding filament model of muscle contraction. (Titin labeled at upper right.)

Titin is a large abundant protein of striated muscle. An 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.[1][2]

Titin interacts with many sarcomeric proteins including:[6]

Clinical relevance

Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9[14][7] and tibial muscular dystrophy.[15] Autoantibodies to titin are produced in patients with the autoimmune disease scleroderma.[16]

Linguistic significance

The name titin (Template:Pron-en) is derived from the Greek Titan (a giant deity, anything of great size).[17]

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.[18][19] However, lexicographers regard generic names of chemical compounds as verbal formulae rather than English words.[20]

Interactions

Titin has been shown to interact with:

References

  1. ^ a b c "Entrez Gene: TTN titin".
  2. ^ a b Labeit S, Barlow DP, Gautel M, Gibson T, Holt J, Hsieh CL, Francke U, Leonard K, Wardale J, Whiting A (1990). "A regular pattern of two types of 100-residue motif in the sequence of titin". Nature. 345 (6272): 273–6. doi:10.1038/345273a0. PMID 2129545. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ a b Labeit S, Kolmerer B (1995). "Titins: giant proteins in charge of muscle ultrastructure and elasticity". Science. 270 (5234): 293–6. doi:10.1126/science.270.5234.293. PMID 7569978. {{cite journal}}: Unknown parameter |month= ignored (help) Cite error: The named reference "pmid7569978" was defined multiple times with different content (see the help page).
  4. ^ Minajeva A, Kulke M, Fernandez JM, Linke WA (2001). "Unfolding of titin domains explains the viscoelastic behavior of skeletal myofibrils". Biophys. J. 80 (3): 1442–51. doi:10.1016/S0006-3495(01)76116-4. PMC 1301335. PMID 11222304. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ Opitz CA, Kulke M, Leake MC, Neagoe C, Hinssen H, Hajjar RJ, Linke WA (2003). "Damped elastic recoil of the titin spring in myofibrils of human myocardium". Proc. Natl. Acad. Sci. U.S.A. 100 (22): 12688–93. doi:10.1073/pnas.2133733100. PMC 240679. PMID 14563922. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  6. ^ a b Bang ML, Centner T, Fornoff F, Geach AJ, Gotthardt M, McNabb M, Witt CC, Labeit D, Gregorio CC, Granzier H, Labeit S (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:10.1161/hh2301.100981. PMID 11717165. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) Cite error: The named reference "pmid11717165" was defined multiple times with different content (see the help page).
  7. ^ a b 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 (2002). "Titin mutations as the molecular basis for dilated cardiomyopathy". Biochem. Biophys. Res. Commun. 291 (2): 385–93. doi:10.1006/bbrc.2002.6448. PMID 11846417. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ Online Mendelian Inheritance in Man (OMIM): 188840
  9. ^ a b "Titin - Homo sapiens (Human)". Universal Protein Resource. UniProt Consortium. 2010-10-05. Retrieved 2010-10-15.
  10. ^ a b c d "ProtParam for human titin". ExPASy Proteomics Server. Swiss Institute of Bioinformatics. Retrieved 2011-07-25.
  11. ^ "ProtParam for mouse titin". ExPASy Proteomics Server. Swiss Institute of Bioinformatics. Retrieved 2010-05-06.
  12. ^ Wang K, McCarter R, Wright J, Beverly J, Ramirez-Mitchell R (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. doi:10.1073/pnas.88.16.7101. PMC 52241. PMID 1714586. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ Bennett PM, Gautel M (1996). "Titin domain patterns correlate with the axial disposition of myosin at the end of the thick filament". J Mol Biol. 259 (5): 896–903. doi:10.1006/jmbi.1996.0367. PMID 8683592. {{cite journal}}: Unknown parameter |month= ignored (help)
  14. ^ Siu BL, Niimura H, Osborne JA, Fatkin D, MacRae C, Solomon S, Benson DW, Seidman JG, Seidman CE (1999). "Familial dilated cardiomyopathy locus maps to chromosome 2q31". Circulation. 99 (8): 1022–6. PMID 10051295. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  15. ^ Hackman P, Vihola A, Haravuori H, Marchand S, Sarparanta J, De Seze J, Labeit S, Witt C, Peltonen L, Richard I, Udd B (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:10.1086/342380. PMC 379188. PMID 12145747. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  16. ^ Machado C, Sunkel CE, Andrew DJ (1998). "Human autoantibodies reveal titin as a chromosomal protein". J. Cell Biol. 141 (2): 321–33. doi:10.1083/jcb.141.2.321. PMC 2148454. PMID 9548712. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  17. ^ Wang K, McClure J, Tu A (1979). "Titin: major myofibrillar components of striated muscle". Proc. Natl. Acad. Sci. U.S.A. 76 (8): 3698–702. doi:10.1073/pnas.76.8.3698. PMC 383900. PMID 291034. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  18. ^ McCulloch S. "Longest word in English". Sarah McCulloch.com. Retrieved 2010-05-24. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  19. ^ "What is the longest word in the English language?". CliffsNotes.com. Retrieved 2009-05-26.
  20. ^ Oxford Word and Language Service team. "Ask the experts - What is the longest English word?". AskOxford.com / Oxford University Press. Retrieved 2008-01-13.
  21. ^ Kontrogianni-Konstantopoulos A, Bloch RJ (2003). "The hydrophilic domain of small ankyrin-1 interacts with the two N-terminal immunoglobulin domains of titin". J. Biol. Chem. 278 (6): 3985–91. doi:10.1074/jbc.M209012200. PMID 12444090. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: unflagged free DOI (link)
  22. ^ a b Miller MK, Bang ML, Witt CC, Labeit D, Trombitas C, Watanabe K, Granzier H, McElhinny AS, Gregorio CC, Labeit S (2003). "The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules". J. Mol. Biol. 333 (5): 951–64. doi:10.1016/j.jmb.2003.09.012. PMID 14583192. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  23. ^ Ono Y, Shimada H, Sorimachi H, Richard I, Saido TC, Beckmann JS, Ishiura S, Suzuki K (1998). "Functional defects of a muscle-specific calpain, p94, caused by mutations associated with limb-girdle muscular dystrophy type 2A". J. Biol. Chem. 273 (27): 17073–8. doi:10.1074/jbc.273.27.17073. PMID 9642272. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  24. ^ Sorimachi H, Kinbara K, Kimura S, Takahashi M, Ishiura S, Sasagawa N, Sorimachi N, Shimada H, Tagawa K, Maruyama K (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. 270 (52): 31158–62. doi:10.1074/jbc.270.52.31158. PMID 8537379. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  25. ^ Lange S, Auerbach D, McLoughlin P, Perriard E, Schäfer BW, Perriard JC, Ehler E (2002). "Subcellular targeting of metabolic enzymes to titin in heart muscle may be mediated by DRAL/FHL-2". J. Cell. Sci. 115 (Pt 24): 4925–36. doi:10.1242/jcs.00181. PMID 12432079. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  26. ^ Young P, Ehler E, Gautel M (2001). "Obscurin, a giant sarcomeric Rho guanine nucleotide exchange factor protein involved in sarcomere assembly". J. Cell Biol. 154 (1): 123–36. doi:10.1083/jcb.200102110. PMC 2196875. PMID 11448995. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  27. ^ Gregorio CC, Trombitás K, Centner T, Kolmerer B, Stier G, Kunke K, Suzuki K, Obermayr F, Herrmann B, Granzier H, Sorimachi H, Labeit S (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. 143 (4): 1013–27. doi:10.1083/jcb.143.4.1013. PMC 2132961. PMID 9817758. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  28. ^ Mayans O, van der Ven PF, Wilm M, Mues A, Young P, Fürst DO, Wilmanns M, Gautel M (1998). "Structural basis for activation of the titin kinase domain during myofibrillogenesis". Nature. 395 (6705): 863–9. doi:10.1038/27603. PMID 9804419. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  29. ^ Zou P, Gautel M, Geerlof A, Wilmanns M, Koch MH, Svergun DI (2003). "Solution scattering suggests cross-linking function of telethonin in the complex with titin". J. Biol. Chem. 278 (4): 2636–44. doi:10.1074/jbc.M210217200. PMID 12446666. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  30. ^ Mues A, van der Ven PF, Young P, Fürst DO, Gautel M (1998). "Two immunoglobulin-like domains of the Z-disc portion of titin interact in a conformation-dependent way with telethonin". FEBS Lett. 428 (1–2): 111–4. doi:10.1016/S0014-5793(98)00501-8. PMID 9645487. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  31. ^ Centner T, Yano J, Kimura E, McElhinny AS, Pelin K, Witt CC, Bang ML, Trombitas K, Granzier H, Gregorio CC, Sorimachi H, Labeit S (2001). "Identification of muscle specific ring finger proteins as potential regulators of the titin kinase domain". J. Mol. Biol. 306 (4): 717–26. doi:10.1006/jmbi.2001.4448. PMID 11243782. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

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. doi:10.1016/S0006-2952(98)00095-1. PMID 9763216.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • 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:10.1007/BF02346659. PMID 10396137. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  • Trinick J, Tskhovrebova L (1999). "Titin: a molecular control freak". Trends Cell Biol. 9 (10): 377–80. doi:10.1016/S0962-8924(99)01641-4. 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • 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:10.1098/rstb.2001.1028. PMC 1692937. 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:10.1074/jbc.R400023200. PMID 15322090.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • 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:10.1054/jcaf.2002.129278. PMID 12555133.{{cite journal}}: CS1 maint: multiple names: authors list (link)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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