What is titin protein
Fascinating giant molecule
In addition to myosin and actin, titin plays an essential role in the ensemble of muscle proteins. The huge molecule - it has a molecular weight of three megadaltons - provides both stability and elasticity in the muscle. However, not all of the functions of the multifaceted protein are still known. Wolfgang Linke and his working group at the Institute for Physiology and Pathophysiology are researching the fascinating giant molecule.
A characteristic feature of almost all animal organisms is the ability to move. The way of movement can be very diverse. The speed of movement also varies considerably: Just think of the slow crawling of a snail compared to the ultra-fast vibration of an insect flight muscle, which oscillates astonishing 1000 times per second. The human heart muscle beats two billion times continuously in the course of a lifetime; the skeletal muscles not only enable us to move, but also to speak, gesticulate, in short, the exchange of thoughts and experiences. From a molecular point of view, the different functions of all these muscles are based on a single common mechanism: the interaction of two proteins, myosin and actin.
Both muscle proteins form stiff structures, so-called filaments. Similar to the bristles of a miniature brush, the filaments are arranged three-dimensionally in the cell, with actin and myosin each forming their own "brushes". In the muscle cell, the "bristles" of the actin and myosin brushes are, as it were, nested into one another: a regular structure is created, the "sarcomere". With a length of two thousandths of a millimeter, the sarcomere is the smallest functional unit of the heart or skeletal muscle cell. Millions of sarcomeres can occur one behind the other in a muscle fiber. It has been known for decades that when muscles contract, actin and myosin filaments slide towards each other. The sarcomeres shorten in the process. When the muscle stretches, the sarcomeres elongate. The length of the individual filaments, however, always remains unchanged.
This description of the molecular processes in muscles is greatly simplified. In addition to myosin and actin, there are many other proteins that take on important functions in muscle contraction in the sarcomere or elsewhere in the cell. One protein in particular plays a central role in the ensemble of sarcomere proteins: titin. Known for around 20 years, it has only recently become clear what extraordinary importance the molecule has. For example, it helps explain why sarcomeres don't fall apart when stretched too much. Or how with a stretching independent of the actin-myosin interaction, a spring force arises that pulls the muscle - and also an isolated sarcomere - back to its original length after the end of the stretching.
The story of Titin begins in the late 1970s. At that time it was possible to identify a filamentous protein that could be associated with the properties mentioned above. It turned out that this protein is larger than any known muscle protein. Paradoxically, precisely because of its size, it was overlooked for a long time: the protein has too little mobility in the usual gel electrophoresis and cannot be detected; it is only displayed when extremely thin gels are used. Because of its huge molecular weight of three megadaltons, the protein was named titin. It is the third most abundant muscle protein after myosin and actin and represents an impressive 400 grams of the body weight of an adult man.
The discovery of titin was initially hardly noticed by muscle researchers. But it soon turned out that titin had to be a very special molecule: In the sarcomere it forms an independent filament system; the protein strands of the titin run through a semi-sarcomere and are about a thousandth of a millimeter long - an astonishing length for a single molecule. However, it was not until the mid-1990s that the concept of the sarcomere as a three-filament system with myosin, actin and titin was generally accepted. The decisive factor was the publication of the amino acid sequence (the order of the building blocks = amino acids of a protein) of the human heart and skeletal muscle titin in 1995 - by the way, by Heidelberg scientists at the European Molecular Biology Laboratory. They proved the existence of a polypeptide approximately 30,000 amino acid residues in size. The renowned American science magazine "Science" honored this milestone with the award of the title "Protein of the Year".
|A muscle is structured hierarchically. Its building blocks are the sarcomeres, whose "backbone" is formed by gigantic titin molecules.|
Since then, the field of titin research has experienced a rapid increase in knowledge. The titin molecule resembles a chain of pearls, so-called globular domains. In total, titin contains up to 300 such domains. They make up about 90 percent of the sequence; the remaining ten percent consists of non-globular sections. Most of the domains bind to other proteins in the sarcomere, especially myosin. It is obvious that these titin areas have an important stabilizing and structural function. It is even believed that titin could be a "molecular ruler" that determines the extremely constant length of the myosin filaments in the sarcomere. If the binding properties of the sarcomere proteins are changed, this can lead to dramatic disorders of muscle function. For example, changes in a protein that anchors both myosin and titin are known. The affected patients suffer from a hereditary heart disease that can lead to sudden cardiac death.
In order to hold the sarcomere together when stretched, the titin filaments would have to connect not only with myosin, but also with actin. This is exactly what my working group was able to demonstrate a few years ago. The binding occurs at that end of the actin filament that does not overlap with myosin. Titin thus connects actin and myosin filaments without preventing them from sliding into one another. The experimental finding is astonishing that when certain domains of the myocardium titin are functionally deactivated, most sarcomeres no longer form actin filaments. Even so, the sarcomeres don't just fall apart: titin and myosin hold them together. Such sarcomeres can no longer contract. On the one hand, titin has a structure-retaining effect in the heart muscle, on the other hand, it contributes significantly to maintaining the force of contraction. Possible disturbances of these titanium functions in the human heart will be of particular interest to us in the future.
At this point it is no longer surprising that the titin filaments are responsible for the elastic properties of the sarcomere - and ultimately of the muscle. However, only that part of the titin that is not bound to myosin or actin contributes to elasticity.
Initial ideas about the nature of the elasticity of titin assumed that the domains of titin unfold when sarcomere stretching, which should explain the increase in length and strength. In fact, impressive, technically complex force measurements on individual titin molecules have shown that the domains are potentially capable of this. In my working group, however, people were skeptical about this "development concept". Because the forces that are necessary for the domains to unfold were, according to our measurements, well above the forces that a sarcomere experiences when the muscle is naturally stretched. In our measurements, it was important to us to determine the elasticity of titin in its natural environment - on the isolated, structurally intact sarcomere. With such experiments we were recently able to prove that unfolding of the titin domains in the sarcomere is rather unlikely. At most, the pathologically overstretched heart or skeletal muscle can develop over a large area, which has a catastrophic effect on the sarcomere structure. The non-globular sections of the molecule are primarily responsible for the physiologically relevant ductility of titin. These sections, which have not yet been defined in more detail in terms of their spatial structure, are also of interest because they occur in different muscle types in different lengths: Heart muscle titin contains short, skeletal muscle titin longer sections.
This explains why the sarcomeres of the skeletal muscles are much more elastic than those of the heart muscle: In contrast to the muscles of the skeleton, the heart muscle needs a high degree of rigidity in order to offer sufficient resistance to the influx of blood in the diastole. Since molecular changes in titin have been described in some heart diseases, we are currently investigating whether these changes affect the elastic regions and affect the mechanical activity of the heart.
By no means all aspects of the titin structure and function could be dealt with here. One surprising discovery should be mentioned, however. A protein that is apparently identical to titin appears to exist in a completely different place: in the chromosomes of the fruit fly. A multifunctional protein like titin could give stability and elasticity not only to muscles but also to chromosomes. It seems that not all roles of the fascinating giant molecule have been uncovered by a long way.
Priv.-Doz. Dr. Wolfgang Linke
Institute for Physiology and Pathophysiology, Im Neuenheimer Feld 326, 69120 Heidelberg,
Telephone (0 62 21) 54 40 54, fax (0 62 21) 54 40 49, email: [email protected]
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