The three-dimensional structure of a type I module from titin. PDB rendering based on 1bpv.
Symbols TTN; CMD1G; CMH9; CMPD4; DKFZp451N061; EOMFC; FLJ26020; FLJ26409; FLJ32040; FLJ34413; FLJ39564; FLJ43066; HMERF; LGMD2J; TMD
External IDs OMIM188840 MGI98864 HomoloGene26418 GeneCards: TTN Gene
EC number
RNA expression pattern
PBB GE TTN 208195 at tn.png
More reference expression data
Species Human Mouse
Entrez 7273 22138
Ensembl ENSG00000155657 ENSMUSG00000051747
UniProt Q8WZ42 A2ASS6
RefSeq (mRNA) NM_003319.4 NM_011652
RefSeq (protein) NP_003310.4 NP_035782
Location (UCSC) Chr 2:
179.39 – 179.7 Mb
Chr 2:
76.54 – 76.82 Mb
PubMed search [1] [2]

Titin (play /ˈttɪn/), 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 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]



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.
Q8WZ42-7 cardiac novex-2 27,118
Q8WZ42-8 cardiac novex-1 27,051


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]


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 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]


Titin has been shown to interact with:


  1. ^ a b c "Entrez Gene: TTN titin". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7273. 
  2. ^ a b Labeit S, Barlow DP, Gautel M, Gibson T, Holt J, Hsieh CL, Francke U, Leonard K, Wardale J, Whiting A (May 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. 
  3. ^ a b Labeit S, Kolmerer B (October 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. 
  4. ^ Minajeva A, Kulke M, Fernandez JM, Linke WA (March 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1301335. 
  5. ^ Opitz CA, Kulke M, Leake MC, Neagoe C, Hinssen H, Hajjar RJ, Linke WA (October 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=240679. 
  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 (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:10.1161/hh2301.100981. PMID 11717165. 
  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 (February 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. 
  8. ^ Online 'Mendelian Inheritance in Man' (OMIM) 188840
  9. ^ a b "Titin - Homo sapiens (Human)". Universal Protein Resource. UniProt Consortium. 2010-10-05. http://www.uniprot.org/uniprot/Q8WZ42. Retrieved 2010-10-15. 
  10. ^ a b c d "ProtParam for human titin". ExPASy Proteomics Server. Swiss Institute of Bioinformatics. http://web.expasy.org/cgi-bin/protparam/protparam1?Q8WZ42@1-34350@. Retrieved 2011-07-25. 
  11. ^ "ProtParam for mouse titin". ExPASy Proteomics Server. Swiss Institute of Bioinformatics. http://www.expasy.org/cgi-bin/protparam1?A2ASS6@noft@. Retrieved 2010-05-06. 
  12. ^ 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. doi:10.1073/pnas.88.16.7101. PMC 52241. PMID 1714586. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=52241. 
  13. ^ Bennett PM, Gautel M (June 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. 
  14. ^ 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. 
  15. ^ 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:10.1086/342380. PMC 379188. PMID 12145747. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=379188. 
  16. ^ Machado C, Sunkel CE, Andrew DJ (April 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2148454. 
  17. ^ Wang K, McClure J, Tu A (August 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=383900. 
  18. ^ McCulloch S. "Longest word in English". Sarah McCulloch.com. http://www.sarahmcculloch.com/luminaryuprise/longest-word.html. Retrieved 2010-05-24. 
  19. ^ "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. 
  20. ^ 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. 
  21. ^ Kontrogianni-Konstantopoulos A, Bloch RJ (February 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. 
  22. ^ a b Miller MK, Bang ML, Witt CC, Labeit D, Trombitas C, Watanabe K, Granzier H, McElhinny AS, Gregorio CC, Labeit S (November 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. 
  23. ^ Ono Y, Shimada H, Sorimachi H, Richard I, Saido TC, Beckmann JS, Ishiura S, Suzuki K (July 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. 
  24. ^ Sorimachi H, Kinbara K, Kimura S, Takahashi M, Ishiura S, Sasagawa N, Sorimachi N, Shimada H, Tagawa K, Maruyama K (December 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. 
  25. ^ Lange S, Auerbach D, McLoughlin P, Perriard E, Schäfer BW, Perriard JC, Ehler E (December 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. 
  26. ^ Young P, Ehler E, Gautel M (July 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2196875. 
  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 (November 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2132961. 
  28. ^ Mayans O, van der Ven PF, Wilm M, Mues A, Young P, Fürst DO, Wilmanns M, Gautel M (October 1998). "Structural basis for activation of the titin kinase domain during myofibrillogenesis". Nature 395 (6705): 863–9. doi:10.1038/27603. PMID 9804419. 
  29. ^ Zou P, Gautel M, Geerlof A, Wilmanns M, Koch MH, Svergun DI (January 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. 
  30. ^ Mues A, van der Ven PF, Young P, Fürst DO, 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. 428 (1–2): 111–4. doi:10.1016/S0014-5793(98)00501-8. PMID 9645487. 
  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 (March 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. 

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