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Introduction
Titin, (TITN) also known as Connectin (PDB 3b43) is a human protein, unique for its large size. It is the largest known protein chain in the entire human body, comprising over 34,000 amino acids and holding a molecular weight of 3800 kD. Titin is found within muscle fibers and classified as a connectin protein. An adult human that weighs 80 kg may contain almost half a kilogram of Titin, making it extremely abundant as well. [3] Due to its abundance and overall importance to human musculature Titin is exceedingly important and vital to understand.
Test 2 [3]
Discovery
The discovery of Titin first began in 1949 as the Australian scientists -- Draper and Hodge -- announced their findings of the first high resolution electron microscope images of striated muscle. [4] From this imaging it was theorized that there were three strands that comprise striated muscles, but after a multitude of papers began to be published on the two filament theory, it quickly became widely accepted. It took until 1986 for the advancement of Atomic Force Microscopy to fully differentiate and view the large protein which was measured to be greater than 10^6 Da and longer than 1 micrometer. [4] This idea is interesting although Titin had been imaged for more than 30 years before it was officially identified and named. It seemingly was ignored due to the popularity of a two filament system as the Actin and Myosin slide and pull over each other. It is now known that Titin is a structural aid that helps with elasticity, although it technically is the ‘third filament.’
Structure
Titin is the largest human protein, being greater than one micrometer in length and comprising more than 34,000 amino acids. Electron microscopy has revealed that the shape of the protein appeared rod-like and had a beaded substructure. [3] As found with most proteins, the structure is fundamental in the function of the protein itself. Being a long rod-like shape aids in the proteins main function of providing elasticity and unidirectional strength in muscle tissue.
Using monoclonal antibodies to map different parts of the protein, the discovery of the PEVK region was uncovered. This PEVK region is located near the I-Band (N-terminus of protein chain) composed mainly of Proline (P), Glutamate (E), Valine (V), and Lysine (K). [5] It is theorized that the length of the PEVK region is related to the elasticity as the PEVK region easily stretches. In Skeletal muscle, the PEVK region contains 2174 residues, while cardiac muscle contains a much shorter region; as short as 163 residues. [5] Within the PEVK region, there is a pattern of super-repeats containing both Immunoglobulins and Fibronectin Type 3 molecules. The N-terminus found in the I-band only had Immunoglobulins though the C-Terminus has both. [5]
Another unique aspect of Titin structure is the ability to uncoil itself aiding in pliability. The way that Titin can physically elongate itself is due to the immunoglobulin domains unfolding and extending. A complete uncoiling can increase peak length up to 29.7 ± 0.4 n. [6]This mechanism of extension is a result of disulfide isomerization reactions within the itself. [7] To complete these isomerization reactions, a sequence analysis [7] showed that up to 21% of Titin’s I-band immunoglobulin domains contained a conserved Cysteine triad enabling the engagement of disulfide isomerization reactions. The ability to unfold itself aids in elasticity, while protein folding will decrease the effective length and increase stiffness.
Titin interacts with other proteins as well, which can seem obvious as it is mainly encountered within muscle fibers which are full of protein. One such protein, Telethonin (PDB 1ya5) , acts as a glue, holding two neighboring Titin particles together at their Ig domains. [8] Telethonin is important to the overall muscle fiber structure of the entire sarcomere, holding TItin molecules together linearly contributes to the parallel structure of striated muscle. The connection of the two Titin molecules are connected in a palindromic arrangement, using a 2:1 assembly of two Titin molecules to one Telethonin. [6] It is theorized through molecular dynamics that there is a series of hydrogen bonds that allow for stabilization of the Titin - Telethonin complex. These hydrogen bonds are very strong providing a tight attachment at the two N-terminals which line up nearest each other as previously stated, in a palindromic fashion. [6] An extremely high force is required to break these bonds which aids itself to the main function of Titin providing structure and strength to muscle sarcomeres.
Function
Medical Importance
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