Titin

Titin (/ˈtaɪtɪn/; also called connectin) is a protein that in humans is encoded by the TTN gene. The protein, which is over 1 μm in length, 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. These domains unfold when the protein is stretched and refold when the tension is removed.

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. 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.

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

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. In 1977, Koscak Maruyama and coworkers isolated an elastic protein from muscle fiber that 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 that they named titin.

In 1990, Siegfried Labeit isolated a partial cDNA clone of titin. Five years later, Labeit and Bernhard Kolmerer determined the cDNA sequence of human cardiac titin. In 2001, Labeit and colleagues determined the complete sequence of the human titin gene.

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). 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.

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

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 3,816,030.05 Da. Its mouse homologue is even larger, comprising 35,213 amino acids with a molecular weight of 3,906,487.6 Da. It has a theoretical isoelectric point of 6.02, and its chemical formula is C_169,719H_270,374N_45,688O_52,238S₉₁₁. It has a theoretical instability index (II) of 42.38, classifying the protein as unstable. 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).