User:Lindsey Pacanowski/Sandbox 1

Relevance

The protein , which is also known as connectin, is a very large type of elastic protein that is found in striated muscles. It is more specifically found in the sarcomere of striated muscle. It is the third most abundant protein in human skeletal muscles. It plays a major role in the flexion and extension of muscles. Titin is considered a structural and mechanical protein in the sarcomere of muscles. It is integral to the structural integrity of sarcomeres and the physiological length range of the sarcomere. It sits at the ends of the thick filament to stabilize it in between the thin filament and helps to create the lattice between the filaments. It was found that titin regulates the length of striated muscle thick filament and is critical for muscle health. There are usually at least six titin proteins in a sarcomere with three on either side of the M-line. In contrast to other sarcomeric proteins that have multiple genes that encode them, titin only has one coding gene. This gene is called TTN, which makes the instructions to build titin. There are predicted to be 363 exons that are included in this gene. Exons 1-251 code for the Z- disc and I- band regions of the titin protein. Exons 252-363 are used to code for the A-band region of the titin protein. There are mutations within this gene that can lead to diseases such as muscular dystrophy. This is due to the mutation in the gene which alters the function of titin and can cause weakness and loss of function of the protein over time. Mutations of the protein can lead to diseases such as dilated cardiomyopathy, which is a condition where the heart muscles weaken. This is caused by isoforms of titin that are less stiff than other isoforms of the protein that are more prevalent in the heart muscles and cause muscle weakness over time. Isoforms are very similar protein variants that are made from the same gene that have subtle genetic differences.

Structure

One of the most interesting facts about the protein titin is that it is the largest known human protein in the world. Titin measures more than one micrometer long and has a molecular weight of 3.0- 3.7 MDa. It consists of over 34,000 amino acids. The protein is made of one polypeptide chain. The amino acids are folded into a linear array of fibronectin and immunoglobulin domains. Titin is anchored in the z-disc and extends to the m-line region of the sarcomere. It is the third filament system found in the sarcomere along with thick and thin filaments. The protein spans half the distance of the sarcomere. In humans the TTN gene encodes for the two regions of this protein. The first region is the I-band which is located in the N-terminal region and the second is the A-band which is located in the C-terminal region. The I-band is considered the flexible part of the protein. It contains two regions of tandem immunoglobulin domains. These are arranged in . These two domains sit on each side of the . The PEVK region includes mostly glutamate, lysine,proline, and valine. The I-band connects to sarcomere at the Z-line. It interacts with actin and alpha-actinin. The A-band consists of a mixture of fibronectin and immunoglobulin repeats. It contains more than 240 of these tandem repeats. These repeats are typically around 10 nm in length. The A-band also has kinase activity. This kinase activity is used for signaling, as well as the functions of the protein as a molecular spring. The molecular spring function of this protein allows for elasticity, post-contraction recoiling, and protects against overextension of the protein. There are also two major isoforms, or protein variants, of titin caused by the differential splicing of the TTN gene. There is a shorter and stiffer isoform which is called N2B. As well as a longer and more flexible isoform called N2BA. This isoform typically has different variants in fetuses but the variation is usually lost once adulthood is reached. The ratio of N2B to N2BA expression in human adults is approximately 0.56 normally. In larger mammals there is more N2BA found than smaller mammals due to the stiffer isoform N2B being better at faster recoil and is more effective for rapid heartrates of smaller mammals.

Function

Titin functions mostly as a molecular spring within the sarcomere in muscle cells. By acting as a spring in the sarcomere, titin is able to maintain the structural arrangement of the thick and thin filaments. It also helps with muscle stiffness. This is an important role because titin helps with the rigidity and relaxation of muscles. During passive force, which is opposing forces extending the sarcomere, titin is very flexible and has fewer bending motions. Without passive force, the titin molecule has more thermally driven bending motions that shorten it to the point of being near zero in length. This pulls the z-discs together and shortens the length of the sarcomere. When the protein is being stretched or condensed, the elastic I-band keeps the A-band centered in the sarcomere. During stretching the immunoglobulin domains straighten and the PEVK domain of the polypeptide partially unfolds. This lowers the entropy and allows enough energy for elastic recoil. Titin is also used to keep continuity between sarcomeres in the striated muscle. This is due to the connections between the z-line and the thick filaments.