Titin /ˈtaɪtɪn/, often known as connectin, is a protein that in people is encoded by the TTN gene.[5][6] Titin is a big protein, better than 1 µm in size,[7] that capabilities as a molecular spring which is liable for the passive elasticity of muscle. It contains 244 individually folded protein domains linked by unstructured peptide sequences.[8] These domains unfold when the protein is stretched and refold when the stress is eliminated.[9]
Titin is essential within the contraction of striated muscle tissues. It connects the Z line to the M line within the sarcomere. The protein contributes to pressure transmission on the Z line and resting pressure within the I band area.[10] It limits the vary of movement of the sarcomere in pressure, thus contributing to the passive stiffness of muscle. Variations within the sequence of titin between various kinds of muscle (e.g., cardiac or skeletal) have been correlated with variations within the mechanical properties of those muscle tissue.[5][11]
Titin is the third most plentiful protein in muscle (after myosin and actin), and an grownup human accommodates roughly 0.5 kg of titin.[12] With its size of ~27,000 to ~35,000 amino acids (relying on the splice isoform), titin is the most important recognized protein.[13] Moreover, the gene for titin accommodates the most important variety of exons (363) found in any single gene,[14] in addition to the longest single exon (17,106 bp).
Contents
Discovery[edit]
Reiji Natori in 1954 was the primary to suggest an elastic construction in muscle fiber to account for the return to the resting state when muscle tissue are stretched after which launched.[15] In 1977, Koscak Maruyama and coworkers remoted an elastic protein from muscle fiber which they referred to as connectin.[16] Two years later, Kuan Wang and coworkers recognized a doublet band on electrophoresis gel similar to a excessive molecular weight, elastic protein which they named titin.[17][18]
Siegfried Labeit in 1990 remoted a partial cDNA clone of titin.[6] In 1995, Labeit and Bernhard Kolmerer decided the cDNA sequence of human cardiac titin.[8] Labeit and colleagues in 2001 decided the whole sequence of the human titin gene.[14][19]
Genomics[edit]
The human gene encoding for titin is situated on the lengthy arm of chromosome 2 and accommodates 363 exons, which collectively code for 38,138 residues (4200 kDa).[14] Throughout the gene are discovered numerous PEVK (proline-glutamate-valine-lysine -abundant structural motifs) exons 84 to 99 nucleotides in size which code for conserved 28- to 33-residue motifs which can signify structural models of the titin PEVK spring. The variety of PEVK motifs within the titin gene seems to have elevated throughout evolution, apparently modifying the genomic area liable for titin’s spring properties.[20]
Isoforms[edit]
Quite a few titin isoforms are produced in numerous striated muscle tissues on account of different splicing.[21] All however one among these isoforms are within the vary of ~27,000 to ~36,000 amino acid residues in size. The exception is the small cardiac novex-3 isoform, which is just 5,604 amino acid residues in size. The next desk lists the recognized titin isoforms:
Construction[edit] – “what is the largest protein”
Titin is the most important recognized protein; its human variant consists of 34,351 amino acids, with the molecular weight of the mature “canonical” isoform of the protein being roughly 3,816,188.13 Da.[22] Its mouse homologue is even bigger, comprising 35,213 amino acids with a MW of three,906,487.6 Da.[23] It has a theoretical isoelectric level of 6.01.[22] The protein’s empirical chemical components 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 quantity of protein in a cell to interrupt down after its synthesis within the cell, is predicted to be roughly 30 hours (in mammalian reticulocytes).[21]
The titin protein is situated between the myosin thick filament and the Z disk.[25] Titin consists primarily of a linear array of two forms of modules, additionally known as protein domains (244 copies in complete): kind I fibronectin kind III area (132 copies) and kind II immunoglobulin area (112 copies).[12][8] Nevertheless, the precise variety of these domains is completely different in numerous species. This linear array is additional organized into two areas:
The C-terminal area additionally accommodates a serine kinase area[27][28] that’s primarily recognized for adapting the muscle to mechanical pressure.[29] It’s “stretch-sensitive” and helps restore overstretching of the sarcomere.[30] The N-terminal (the Z-disc finish) accommodates a “Z repeat” that acknowledges Actinin alpha 2.[31]
The elasticity of the PEVK area has each entropic and enthalpic contributions and is characterised by a polymer persistence size and a stretch modulus.[33] At low to reasonable extensions PEVK elasticity will be modeled with a normal worm-like chain (WLC) mannequin of entropic elasticity. At excessive extensions PEVK stretching will be modeled with a modified WLC mannequin that comes with enthalpic elasticity. The distinction between low-and high- stretch elasticity is because of electrostatic stiffening and hydrophobic results.
Evolution[edit]
The titin domains have advanced from a standard ancestor via many gene duplication occasions.[34] Area duplication was facilitated by the truth that most domains are encoded by single exons. Different big sarcomeric proteins made out of Fn3/Ig repeats embody obscurin and myomesin. All through evolution, titin mechanical energy seems to lower via the lack of disulfide bonds because the organism turns into heavier.[35]
Titin A-band has homologs in invertebrates, resembling twitchin (unc-22) and projectin, which additionally include Ig and FNIII repeats and a protein kinase area.[30] The gene duplication occasions occurred independently however had been from the identical ancestral Ig and FNIII domains. It’s stated that the protein titin was the primary to diverge out of the household.[28] Drosophila projectin, formally often called bent (bt), is related to lethality by failing to flee the egg in some mutations in addition to dominant adjustments in wing angles.[36][37][38]
Drosophila Titin, often known as Kettin or sallimus (sls), is kinase-free. It has roles within the elasticity of each muscle and chromosomes. It’s homologous to vertebrate titin I-band and accommodates Ig PEVK domains, the various repeats being a scorching goal for splicing.[39] There additionally exists a titin homologue, ttn-1, in C. elegans.[40] It has a kinase area, some Ig/Fn3 repeats, and PEVT repeats which can be equally elastic.[41]
Perform[edit]
Titin is a big plentiful protein of striated muscle. Titin’s main capabilities are to stabilize the thick filament, middle it between the skinny filaments, forestall overstretching of the sarcomere, and to recoil the sarcomere like a spring after it’s stretched.[42] An N-terminal Z-disc area and a C-terminal M-line area bind to the Z-line and M-line of the sarcomere, respectively, so {that a} single titin molecule spans half the size of a sarcomere. Titin additionally accommodates binding websites for muscle-associated proteins so it serves as an adhesion template for the meeting of contractile equipment in muscle cells. It has additionally been recognized as a structural protein for chromosomes.[43][44] Appreciable variability exists within the I-band, the M-line and the Z-disc areas of titin. Variability within the I-band area contributes to the variations in elasticity of various titin isoforms and, subsequently, to the variations in elasticity of various muscle sorts. Of the various titin variants recognized, 5 are described with full transcript data obtainable.[5][6]
Dominant mutation in TTN causes predisposition to hernias.[45]
Titin interacts with many sarcomeric proteins together with:[14]
“what is the largest protein”