Titin
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RefSeq (protein) |
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Location (UCSC) | Chr 2: 178.53 – 178.83 Mb | Chr 2: 76.7 – 76.98 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Titin[5] /ˈtaɪtɪn/ (contraction for Titan protein) (also called connectin) is a protein that in humans is encoded by the TTN gene.[6][7] Titin is a protein, over 1 µm in length,[8] that functions as a molecular spring that is responsible for the passive elasticity of muscle. It comprises 244 individually folded protein domains connected by unstructured peptide sequences.[9] These domains unfold when the protein is stretched and refold when the tension is removed.[10]
Titin is important in the contraction of striated muscle tissues. It connects the Z disc to the M line in the sarcomere. The protein contributes to force transmission at the Z disc and resting tension in the I band region.[11] 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 striated muscle (cardiac or skeletal) have been correlated with differences in the mechanical properties of these muscles.[6][12]
Titin is the third most abundant protein in muscle (after myosin and actin), and an adult human contains approximately 0.5 kg of titin.[13] With its length of ~27,000 to ~35,000 amino acids (depending on the splice isoform), titin is the largest known protein.[14] Furthermore, the gene for titin contains the largest number of exons (363) discovered in any single gene,[15] as well as the longest single exon (17,106 bp).
Discovery
In 1954, Reiji Natori proposed the existence of an elastic structure in muscle fiber to account for the return to the resting state when muscles are stretched and then released.[16] In 1977, Koscak Maruyama and coworkers isolated an elastic protein from muscle fiber that they called connectin.[17] Two years later, Kuan Wang and coworkers identified a doublet band on electrophoresis gel corresponding to a high molecular weight, elastic protein that they named titin.[5][18]
In 1990, Siegfried Labeit isolated a partial
Genetics
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 amino acid residues (4200 kDa).[15] 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 that 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:
Isoform | Alias/description | Length | Molecular weight |
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Q8WZ42-1 | The "canonical" sequence | 34,350 | 3,816,030 |
Q8WZ42-2 | 34,258 | 3,805,708 | |
Q8WZ42-3 | Small cardiac N2-B | 26,926 | 2,992,939 |
Q8WZ42-4 | Soleus | 33,445 | 3,716,027 |
Q8WZ42-5 | 32,900 | 3,653,085 | |
Q8WZ42-6 | Small cardiac novex-3 | 5,604 | 631,567 |
Q8WZ42-7 | Cardiac novex-2 | 33,615 | 3,734,648 |
Q8WZ42-8 | Cardiac novex-1 | 34,475 | 3,829,846 |
Q8WZ42-9 | 27,118 | 3,013,957 | |
Q8WZ42-10 | 27,051 | 3,006,755 | |
Q8WZ42-11 | 33,423 | 3,713,600 | |
Q8WZ42-12 | 35,991 | 3,994,625 | |
Q8WZ42-13 | 34,484 | 3,831,069 |
Structure
Titin is the largest known protein; its human variant consists of 34,350
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).[13][9] 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 that 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
The elasticity of the PEVK region has both
Embedded between the PEVK and Ig residues are N2A domains.[33]
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 | |||||||||
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Identifiers | |||||||||
Symbol | Titin_Ig-rpts | ||||||||
Pfam | PF06582 | ||||||||
InterPro | IPR010939 | ||||||||
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Drosophila Titin, also known as Kettin or
Function
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.[6][7]
Dominant mutation in TTN causes predisposition to hernias.[45]
Titin interacts with many sarcomeric proteins including:[15]
- Z line region: alpha-actinin
- I band region: obscurin
- M line region: CAPN3, and MURF1
Clinical relevance
Autoantibodies to titin are produced in patients with the autoimmune disease Myasthenia gravis.[55]
Interactions
Titin has been shown to
Linguistic significance
The name titin is derived from the Greek
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.[66] However, lexicographers regard generic names of chemical compounds as verbal formulae rather than English words.[67]
References
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- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000051747 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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- ^ National Library of Medicine; National Center for Biotechnology Information. April 2018. Archivedfrom the original on 2010-03-07.
- ^ from the original on 22 October 2021. Retrieved 8 May 2022.
- ^ Lee EH. "The Chain-like Elasticity of Titin". Theoretical and Computational Biophysics Group, University of Illinois. Archived from the original on 13 February 2021. Retrieved 25 September 2014.
- ^ from the original on 2 March 2021. Retrieved 8 May 2022.
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- ^ a b "Titin - Homo sapiens (Human)". Universal Protein Resource. UniProt Consortium. 2010-10-05. Archived from the original on 2021-02-13. Retrieved 2010-10-15.
- ^ a b c d "ProtParam for human titin". ExPASy Proteomics Server. Swiss Institute of Bioinformatics. Archived from the original on 2019-09-18. Retrieved 2011-07-25.
- ^ "ProtParam for mouse titin". ExPASy Proteomics Server. Swiss Institute of Bioinformatics. Retrieved 2010-05-06.
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- ^ "Titin, Z repeat (IPR015129) < InterPro < EMBL-EBI". Archived from the original on 13 February 2021. Retrieved 13 March 2019.
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- ^ "bent phenotype". Classical Genetics Simulator. Archived from the original on 11 February 2019. Retrieved 13 March 2019.
- ^ "FlyBase Gene Report: Dmel\bt". flybase.org. Archived from the original on 13 March 2019. Retrieved 13 March 2019.
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- ^ "ttn-1 (gene)". WormBase: Nematode Information Resource. Archived from the original on 27 March 2018. Retrieved 13 March 2019.
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- ^ McCulloch S (December 2009). "Longest word in English". Sarah McCulloch.com. Archived from the original on 2010-01-14. Retrieved 2016-10-12.
- ^ Oxford Word and Language Service team. "Ask the experts - What is the longest English word?". AskOxford.com / Oxford University Press. Archived from the original on 2008-09-13. Retrieved 2008-01-13.
Further reading
- Tskhovrebova L, Trinick J (September 2003). "Titin: properties and family relationships". Nature Reviews. Molecular Cell Biology. 4 (9): 679–689. 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): 415–420. PMID 9763216.
- Kolmerer B, Witt CC, Freiburg A, Millevoi S, Stier G, Sorimachi H, 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". Reviews of Physiology, Biochemistry and Pharmacology. 138: 19–55. PMID 10396137.
- Trinick J, Tskhovrebova L (October 1999). "Titin: a molecular control freak". Trends in Cell Biology. 9 (10): 377–380. 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. Vol. 481. pp. 383–95, discussion 395–7. 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. 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): 46351–46354. 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–S286. PMID 12555133.
External links
- GeneReviews/NIH/NCBI/UW entry on Familial Hypertrophic Cardiomyopathy Overview
- GeneReviews/NCBI/NIH/UW entry on Udd Distal Myopathy, Tibial Muscular Dystrophy, Udd Myopathy
- GeneReviews/NIH/NCBI/UW entry on Salih Myopathy or Early-Onset Myopathy with Fatal Cardiomyopathy
- InterPro domain organization of titin
This article incorporates text from the United States National Library of Medicine, which is in the public domain.