Titin

Titin /ˈtaɪtɪn/, also known as connectin, is a protein that in humans is encoded by the TTN gene.[5][6] Titin is a giant protein, greater than 1 µm in length,[7] that functions as a molecular spring which is responsible for the passive elasticity of muscle. It comprises 244 individually folded protein domains connected by unstructured peptide sequences.[8] These domains unfold when the protein is stretched and refold when the tension is removed.[9]

Not to be confused with Titan, Tintin, or Titian.
TTN
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTTN, CMD1G, CMH9, CMPD4, EOMFC, HMERF, LGMD2J, MYLK5, TMD, titin, SALMY, LGMDR10
External IDsOMIM: 188840 MGI: 98864 HomoloGene: 130650 GeneCards: TTN
EC number2.7.11.1
Gene location (Human)
Chr.Chromosome 2 (human)[1]
Band2q31.2Start178,525,989 bp[1]
End178,830,802 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

7273

22138

Ensembl

ENSG00000155657

ENSMUSG00000051747

UniProt

Q8WZ42

A2ASS6

RefSeq (mRNA)

NM_011652
NM_028004

RefSeq (protein)

NP_035782
NP_082280

Location (UCSC)Chr 2: 178.53 – 178.83 MbChr 2: 76.7 – 76.98 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[10] 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) have been correlated with differences in the mechanical properties of these muscles.[5][11]

Titin is the third most abundant protein in muscle (after myosin and actin), and an adult human contains approximately 0.5 kg of titin.[12] With its length of ~27,000 to ~35,000 amino acids (depending on the splice isoform), titin is the largest known protein.[13] Furthermore, the gene for titin contains the largest number of exons (363) discovered in any single gene,[14] as well as the longest single exon (17,106 bp).

Discovery

Reiji Natori in 1954 was the first to propose an elastic structure in muscle fiber to account for the return to the resting state when muscles are stretched and then released.[15] In 1977, Koscak Maruyama and coworkers isolated an elastic protein from muscle fiber which they called connectin.[16] Two years later, Kuan Wang and coworkers identified a doublet band on electrophoresis gel corresponding to a high molecular weight, elastic protein which they named titin.[17][18]

Siegfried Labeit in 1990 isolated a partial cDNA clone of titin.[6] In 1995, Labeit and Bernhard Kolmerer determined the cDNA sequence of human cardiac titin.[8] Labeit and colleagues in 2001 determined the complete sequence of the human titin gene.[14][19]

Genomics

The human gene encoding for titin is located on the long arm of chromosome 2 and contains 363 exons, which together code for 38,138 residues (4200 kDa).[14] Within the gene are found a large number of PEVK (proline-glutamate-valine-lysine -abundant structural motifs) exons 84 to 99 nucleotides in length which code for conserved 28- to 33-residue motifs which may represent structural units of the titin PEVK spring. The number of PEVK motifs in the titin gene appears to have increased during evolution, apparently modifying the genomic region responsible for titin's spring properties.[20]

Isoforms

A number of titin isoforms are produced in different striated muscle tissues as a result of alternative splicing.[21] All but one of these isoforms are in the range of ~27,000 to ~36,000 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:

Isoformalias/descriptionlengthMW
Q8WZ42-1The "canonical" sequence34,3503,816,030
Q8WZ42-234,2583,805,708
Q8WZ42-3Small cardiac N2-B26,9262,992,939
Q8WZ42-4Soleus33,4453,716,027
Q8WZ42-532,9003,653,085
Q8WZ42-6Small cardiac novex-35,604631,567
Q8WZ42-7Cardiac novex-233,6153,734,648
Q8WZ42-8Cardiac novex-134,4753,829,846
Q8WZ42-927,1183,013,957
Q8WZ42-1027,0513,006,755
Q8WZ42-1133,4233,713,600
Q8WZ42-1235,9913,994,625
Q8WZ42-1334,4843,831,069

Structure

Titin is the largest known protein; its human variant consists of 34,351 amino acids, with the molecular weight of the mature "canonical" isoform of the protein being approximately 3,816,188.13 Da.[22] Its mouse homologue is even larger, comprising 35,213 amino acids with a MW of 3,906,487.6 Da.[23] It has a theoretical isoelectric point of 6.01.[22] The protein's empirical chemical formula is C169,719H270,466N45,688O52,238S911.[22] It has a theoretical instability index (II) of 42.41, classifying the protein as unstable.[22] 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).[21]

Titin Ig domains. a) Schematic of part of a sarcomere b) Structure of Ig domains c) Topology of Ig domains.[24]

The titin protein is located between the myosin thick filament and the Z disk.[25] 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).[12][8] However, the exact number of these domains is different in different species. 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 which is rich in proline (P), glutamate (E), valine (V) and lysine (K).[25]
  • C-terminal A-band: is thought to act as a protein-ruler and is composed of alternating type I (Fn3) and II (Ig) 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.[26]

The C-terminal region also contains a serine kinase domain[27][28] that is primarily known for adapting the muscle to mechanical strain.[29] It is “stretch-sensitive” and helps repair overstretching of the sarcomere.[30] The N-terminal (the Z-disc end) contains a "Z repeat" that recognizes Actinin alpha 2.[31]

Protein domains of Titin A-band. White boxes are Fn3 domains, red boxes are Ig domains, yellow boxes are Fn3 domains with the -AVNKYG- sequence, and the black box is protein kinase domain.[32]

The elasticity of the PEVK region has both entropic and enthalpic contributions and is characterized by a polymer persistence length and a stretch modulus.[33] At low to moderate extensions PEVK elasticity can be modeled with a standard worm-like chain (WLC) model of entropic elasticity. At high extensions PEVK stretching can be modeled with a modified WLC model that incorporates enthalpic elasticity. The difference between low-and high- stretch elasticity is due to electrostatic stiffening and hydrophobic effects.

Evolution

The titin domains have evolved from a common ancestor through many gene duplication events.[34] Domain duplication was facilitated by the fact that most domains are encoded by single exons. Other giant sarcomeric proteins made out of Fn3/Ig repeats include obscurin and myomesin. Throughout evolution, titin mechanical strength appears to decrease through the loss of disulfide bonds as the organism becomes heavier.[35]

Titin A-band has homologs in invertebrates, such as twitchin (unc-22) and projectin, which also contain Ig and FNIII repeats and a protein kinase domain.[30] The gene duplication events took place independently but were from the same ancestral Ig and FNIII domains. It is said that the protein titin was the first to diverge out of the family.[28] Drosophila projectin, officially known as bent (bt), is associated with lethality by failing to escape the egg in some mutations as well as dominant changes in wing angles.[36][37][38]

Titin repeat
Identifiers
SymbolTitin_Ig-rpts
PfamPF06582
InterProIPR010939

Drosophila Titin, also known as Kettin or sallimus (sls), is kinase-free. It has roles in the elasticity of both muscle and chromosomes. It is homologous to vertebrate titin I-band and contains Ig PEVK domains, the many repeats being a hot target for splicing.[39] There also exists a titin homologue, ttn-1, in C. elegans.[40] It has a kinase domain, some Ig/Fn3 repeats, and PEVT repeats that are similarly elastic.[41]

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

Titin is a large abundant protein of striated muscle. Titin's primary functions are to stabilize the thick filament, center it between the thin filaments, prevent overstretching of the sarcomere, and to recoil the sarcomere like a spring after it is stretched.[42] 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.[43][44] 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 are described with complete transcript information available.[5][6]

Dominant mutation in TTN causes predisposition to hernias.[45]

Titin interacts with many sarcomeric proteins including:[14]

Clinical relevance

Mutations anywhere within the unusually long sequence of this gene can cause premature stop codons or other defects. Titin mutations are associated with hereditary myopathy with early respiratory failure, early-onset myopathy with fatal cardiomyopathy, core myopathy with heart disease, centronuclear myopathy, limb-girdle muscular dystrophy type 2J, familial dilated cardiomyopathy 9,[10][46] hypertrophic cardiomyopathy and tibial muscular dystrophy.[47] Further research also suggests that no genetically linked form of any dystrophy or myopathy can be safely excluded from being caused by a mutation on the TTN gene.[48] Truncating mutations in dilated cardiomyopathy patients are most commonly found in the A region; although truncations in the upstream I region might be expected to prevent translation of the A region entirely, alternative splicing creates some transcripts that do not encounter the premature stop codon, ameliorating its effect.[49]

Autoantibodies to titin are produced in patients with the autoimmune disease scleroderma.[43]

Interactions

Titin has been shown to interact with:

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 of a protein. The full chemical name of the human canonical form of titin, which starts methionyl... and ends ...isoleucine, contains 189,819 letters and is sometimes stated to be the longest word in the English language, or of any language.[60] However, lexicographers regard generic names of chemical compounds as verbal formulae rather than English words.[61]

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Further reading
  • Tskhovrebova L, Trinick J (September 2003). "Titin: properties and family relationships". Nature Reviews Molecular Cell Biology. 4 (9): 679–89. doi:10.1038/nrm1198. PMID 14506471. S2CID 12293932.
  • Kinbara K, Sorimachi H, Ishiura S, Suzuki K (August 1998). "Skeletal muscle-specific calpain, p49: structure and physiological function". Biochemical Pharmacology. 56 (4): 415–20. doi:10.1016/S0006-2952(98)00095-1. PMID 9763216.
  • Kolmerer B, Witt CC, Freiburg A, Millevoi S, Stier G, Sorimachi H, Pelin K, Carrier L, Schwartz K, Labeit D, Gregorio CC, Linke WA, Labeit S (1999). "The titin cDNA sequence and partial genomic sequences: insights into the molecular genetics, cell biology and physiology of the titin filament system". Reviews of Physiology, Biochemistry and Pharmacology. 138: 19–55. doi:10.1007/BF02346659. PMID 10396137.
  • Trinick J, Tskhovrebova L (October 1999). "Titin: a molecular control freak". Trends in Cell Biology. 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". Elastic Filaments of the Cell. Advances in Experimental Medicine and Biology. 481. pp. 383–95, discussion 395–7. doi:10.1007/978-1-4615-4267-4_23. ISBN 978-1-4613-6916-5. PMID 10987085.
  • Tskhovrebova L, Trinick J (February 2002). "Role of titin in vertebrate striated muscle". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 357 (1418): 199–206. doi:10.1098/rstb.2001.1028. PMC 1692937. PMID 11911777.
  • Sela BA (July 2002). "[Titin: some aspects of the largest protein in the body]". Harefuah. 141 (7): 631–5, 665. PMID 12187564.
  • Tskhovrebova L, Trinick J (November 2004). "Properties of titin immunoglobulin and fibronectin-3 domains". The Journal of Biological Chemistry. 279 (45): 46351–4. doi:10.1074/jbc.R400023200. PMID 15322090.
  • Wu Y, Labeit S, Lewinter MM, Granzier H (December 2002). "Titin: an endosarcomeric protein that modulates myocardial stiffness in DCM". Journal of Cardiac Failure. 8 (6 Suppl): S276–86. doi:10.1054/jcaf.2002.129278. PMID 12555133.

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