titin

 

  • The following table lists the known titin isoforms: Structure 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.

  • [45] Titin interacts with many sarcomeric proteins including:[15] • Z line region: telethonin and alpha-actinin • I band region: calpain-3 and obscurin • M line region: myosin-binding
    protein C, calmodulin 1, CAPN3, and MURF1 Clinical relevance Mutations anywhere within the unusually long sequence of this gene can cause premature stop codons or other defects.

  • [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.

  • [15][19] 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).

  • 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.

  • 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.

  • [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).

  • [26] The C-terminal region also contains a serine kinase domain[27][28] that is primarily known for adapting the muscle to mechanical strain.

  • It has also been identified as a structural protein for chromosomes.

  • 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.

  • 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).

  • 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.

  • [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.

  • [49] 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.

  • [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).

  • Throughout evolution, titin mechanical strength appears to decrease through the loss of disulfide bonds as the organism becomes heavier.

  • The protein contributes to force transmission at the Z disc and resting tension in the I band region.

  • Other giant sarcomeric proteins made out of Fn3/Ig repeats include obscurin and myomesin.

  • [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.

  • [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.

  • [20] Isoforms A number of titin isoforms are produced in different striated muscle tissues as a result of alternative splicing.

  • [22] Its mouse homologue is even larger, comprising 35,213 amino acids with a molecular weight of 3,906,487.6 Da.

 

Works Cited

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