Titin Titin /ˈtaɪtɪn/, also known as connectin,
is a protein that, in humans, is encoded by the TTN gene. Titin is a giant protein that
functions as a molecular spring which is responsible for the passive elasticity of muscle. It is
composed of 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 line to the M line in the 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) has been correlated with differences in the mechanical properties of these muscles.
With its length of ~27,000 to ~33,000 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). Genomics
The human gene that encodes titin is found on chromosome 2 and contains 363 exons.
Isoforms 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 ~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 amino acids, with the 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
isoelectric point of 6.01. The protein's empirical chemical formula is C169 723H270 464N45 688O52
243S912. It has a theoretical instability index (II) of 42.41, 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). 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).
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. Titin is found between the myosin thick filament and the Z disk.
C-terminal A-band: is thought to act as a protein-ruler and possesses 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 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. 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, calmodulin 1, CAPN3, and MURF1
Clinical relevance Mutations in this gene are associated with
familial dilated cardiomyopathy 9 and tibial muscular dystrophy. Further research also
suggests that no genetically linked form of any dystrophy or myopathy can be safely excluded
from being caused by a mutation on the TTN gene. Autoantibodies to titin are produced
in patients with the autoimmune disease scleroderma. 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. The full chemical
name, which starts methionyl... and ends...isoleucine, contains 189,819 letters and is sometimes
stated to be the longest word in the English language, or any language. It can take over
three hours to pronounce. However, lexicographers regard generic names of chemical compounds
as verbal formulae rather than English words. Interactions
Titin has been shown to interact with: ANK1,
ANKRD1, ANKRD23
CAPN3, FHL2,
OBSCN, TCAP, and
TRIM63.