Titin

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

Titin is important in the contraction of is_associated_with::striated muscle tissues. It connects the Z line to the M line in the is_associated_with::sarcomere. The protein contributes to force transmission at the Z line and resting tension in the I band region. 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.

After is_associated_with::myosin and is_associated_with::actin, titin is the third most abundant protein in muscle and an adult human contains approximately 0.5 kg of titin. With its length of ~27,000 to ~33,000 is_associated_with::amino acids (depending on the splice isoform), titin is the largest known is_associated_with::protein. Furthermore, the gene for titin contains the largest number of is_associated_with::exons (363) discovered in any single gene, 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. In 1977, Koscak Maruyama and coworkers isolated an elastic protein from muscle fiber which they called connectin. 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.

Labeit in 1990 isolated a partial is_associated_with::cDNA clone of titin. In 1995, Labeit and Kolmerer determined the cDNA sequence of human cardiac titin. Bang and coworkers in 2001 determined the complete sequence of the human titin gene.

Genomics
The human gene that encodes titin is found on is_associated_with::chromosome 2 and contains 363 is_associated_with::exons.

Isoforms
A number of titin isoforms are produced in different striated muscle tissues as a result of is_associated_with::alternative splicing. 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:

Structure
Titin is the largest known protein; its human variant consists of 34,350 is_associated_with::amino acids, with the is_associated_with::molecular weight of the mature "canonical" isoform of the protein being approximately 3,816,188.13 Da. Its mouse homologue is even larger, comprising 35,213 amino acids with a MW of 3,906,487.6 Da. It has a theoretical is_associated_with::isoelectric point of 6.01. The protein's empirical is_associated_with::chemical formula is C169 723H270 464N45 688O52 243S912. It has a theoretical is_associated_with::instability index (II) of 42.41, classifying the protein as unstable. The protein's is_associated_with::in vivo is_associated_with::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 is_associated_with::mammalian is_associated_with::reticulocytes).

The titin protein is located between the is_associated_with::myosin thick filament and the Z disk. Titin consists primarily of a linear array of two types of modules (also referred to as is_associated_with::protein domains; 244 copies in total): type I (is_associated_with::fibronectin type III domain; 132 copies) and type II (is_associated_with::immunoglobulin domain; 112 copies). 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.
 * C-terminal A-band: is thought to act as a protein-ruler and possesses is_associated_with::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.

Function
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 is_associated_with::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 is_associated_with::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 are described with complete transcript information available.

Titin interacts with many sarcomeric proteins including:
 * Z line region: telethonin and alpha-actinin
 * I band region: calpain-3 and obscurin
 * M line region: myosin-binding protein C, is_associated_with::calmodulin 1, is_associated_with::CAPN3, and MURF1

Clinical relevance
Mutations in this gene 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 is_associated_with::dilated cardiomyopathy 9, hypertrophic cardiomyopathy and tibial muscular dystrophy. Further research also suggests that no genetically linked form of any dystrophy or is_associated_with::myopathy can be safely excluded from being caused by a is_associated_with::mutation on the TTN gene. Autoantibodies to titin are produced in patients with the autoimmune disease is_associated_with::scleroderma.

Interactions
Titin has been shown to interact with:


 * is_associated_with::ANK1,
 * is_associated_with::ANKRD1,
 * is_associated_with::ANKRD23
 * is_associated_with::CAPN3,
 * is_associated_with::FHL2,
 * is_associated_with::OBSCN,
 * TCAP,   and
 * is_associated_with::TRIM63.

Linguistic significance
The name titin is derived from the Greek Titan (a giant deity, anything of great size).

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 ...is_associated_with::isoleucine, contains 189,819 letters and is sometimes stated to be the longest word in the English language, or any language. However, lexicographers regard generic names of is_associated_with::chemical compounds as verbal formulae rather than English words.