The elastic protein titin consists of approximately 30,000 amino acids, making it the largest known human protein. As a component of sarcomeres, the smallest contractile unit of skeletal and cardiac muscles, titin provides the elastic connection between Z-disks and myosin heads in the form of filaments. Titin filaments are passively preloaded and retract the myosin filaments after a contraction, which is roughly comparable to the function of a preloaded return spring of a machine.
What is titin?
Titin is a comparatively huge, elastic protein with a molecular mass of about 3.6 million daltons, embodying the largest known human protein molecule. Also known as connectin, titin is an important component of striated skeletal and cardiac muscles. When strung together, titin molecules join together to form elastic titin filaments and hold the myosin filaments in position in the sarcomere, the smallest contractile unit of the muscles. After contraction and subsequent relaxation of the muscle, they support the repositioning of the myosin filaments by their elastic pretension. During the resting phase of the muscle, the titin filaments provide a sustained light muscle tension. According to internationally valid rules of the “International Union of Pure and Applied Chemistry” (IUPAC), proteins are named according to the amino acids they contain, namely according to their primary sequence. When this rule is applied to titin, the result is an acronym of nearly 190,000 letters that would take several hours to read.
Anatomy and structure
Within a sarcomere, titin filaments provide the elastic link between contractile myosin filaments and the so-called Z-disks that border each sarcomere at both ends. Each individual myosin filament is connected at each of its ends to a titin filament, each of which is anchored to the Z-disk so that the myosin filaments are held in place by the titin filaments during the resting phase and also during the contraction phase. The approximately 30,000 amino acids are organized into a total of 320 protein domains. Protein domains consist of a sequence of amino acids that could act independently of the rest of the protein molecule as an independent protein or polypeptide and perform physiological functions. Several hundred serially connected sarcomeres form a muscle or myofibril, which in turn combine to form several hundred muscle fibers. Under the light microscope, the individual zones of sarcomeres arranged in parallel and one behind the other are visible as transverse striations. In each case, to the right and left of the dark-appearing Z-disks, the lighter so-called I-bands can be seen, which, in addition to actin filaments, mainly contain the elastic titin.
Function and tasks
The contractile function of a sarcomere, the smallest functional unit within a striated muscle cell, relies on myosin filaments that telescope during muscle contraction, causing the sarcomere to shorten. To ensure that the shortening of the myosin filaments affects the entire muscle, they are connected on both sides with titin filaments, which in turn are anchored to the Z-disks. This means that the titin filaments form an elastic connection between the myosin filaments and the Z-disks. The titin filaments provide a kind of pre-tension to keep the myosin filaments in a central position between the actin filaments surrounding them, both in the relaxed and contracted states. The elasticity of titin ensures that the contraction and relaxation phases of the muscle do not follow one another in a jerky manner, but are slowed down and can be better controlled in terms of fine motor control. Furthermore, the titin filaments counteract injury to the muscle fibers during strong and violent stretching by elastic “yielding”. In addition, the titin filaments increase the total distance a muscle can shorten overall because the titin filaments also shorten during the contraction phase and increase the contractile path length of the sarcomere. During the relaxation phase of the muscle, the action of the titin filaments is comparable to the working principle of a return spring because of their basic tension. The elasticity of the titin thus passively supports the work of the antagonistic muscle, which in principle ensures that the sarcomeres are “pulled” back to their original length.
Diseases
Muscular diseases and complaints that could be attributed to a malfunction of the structural protein titin are not known. Probably the best-known muscular ailment in which titin also plays a role is muscle soreness, which almost everyone encounters one or more times during their lifetime. According to recent findings, muscle soreness is caused by microcracks on the Z-disks of the sarcomeres and the destruction of the holding structures for titin and other proteins involved. Most likely, the typical muscle soreness comes from a reaction of the muscle cells to the mini-injuries. Painful inflammatory reactions are generated, which should enable the rapid repair of the sarcomeres. In connection with muscle soreness, there is still an opinion that it is due to over-acidification of the muscle with lactic acid, an assumption that has since been disproved. Myasthenia gravis is a rare neuromuscular disease in which titin is also involved. It is a disorder of motor signal transmission to muscle cells. Autoantibodies block the acetylcholine receptors of the motor end plate. Autoantibodies target the body’s own tissues or hormones. In most patients suffering from myasthenia gravis, antibodies against the protein fragment MGT30 can be detected. This is a polypeptide with a molecular mass of 30,000 daltons that is contained in titin. Detection of antibodies against a substructure of titin is useful in the differential diagnosis of suspected presence of the autoimmune disease myasthenia gravis.
