Overview
Ttn is a protein that in humans is encoded by the TTN gene. It is the largest known protein, with a molecular weight of around 3 million daltons. It contains 27,280 amino acids and its length varies from individual to individual, but is typically around 14 micrometres (0.55 in). The function of Ttn is not well understood, but it appears to be involved in muscle development and maintenance. Mutations in TTN are associated with several different diseases, including dilated cardiomyopathy (DCM), restrictive cardiomyopathy (RCM), atrial fibrillation (AF), and skeletal muscle disorders such as Emery-Dreifuss muscular dystrophy (EDMD) and limb-girdle muscular dystrophy type 1A (LGMD1A).
TTN was first identified in 1997 as the product of a gene that was upregulated in heart failure. The gene was initially called “heart and neural crest derivatives expressed 2” (HAND2), but the name was changed to “titin” after the discovery that it encodes the largest known protein. The human TTN gene is located on chromosome 2q31 and consists of 363 exons that encode a polypeptide of 27,280 amino acids. The full-length TTN protein has a mass of approximately 3 million daltons and is thought to be composed of four structurally distinct domains: an N-terminal variable domain, two central immunoglobulin domains, and a C-terminal spring domain. The variable domain contains six fibronectin type III repeats that are thought to mediate interactions with other proteins or cell surfaces. The immunoglobulin domains are homologous to those found in antibodies and other proteins involved in immune responses; their function in titin remains unclear. The spring domain forms an elastic scaffold within muscle cells that allows them to withstand stretching forces; mutations in this domain are responsible for many of the muscle disorders associated with TTN mutations .
The role of Ttn in human physiology is not well understood, but it appears to be important for muscle development and maintenance. Ttn mRNA is highly expressed during embryonic development, particularly in skeletal muscles . In adults, Ttn mRNA levels are lower but still detectable throughout the body , although expression levels vary depending on tissue type . For example, Ttn expression is highest in cardiac muscles , followed by skeletal muscles , smooth muscles , brain , kidney , liver , pancreas , spleen , lung , thymus , testis , ovary etc . Several lines of evidence suggest that Ttn plays a role in maintaining normal muscle structure and function . For example, mice lacking functional Ttn show abnormalities in their skeletal muscles ; these abnormalities can be partially rescued by overexpression of another protein called nebulin . In addition, mutations affecting different parts of the Titin molecule lead to different types of muscular dystrophy or cardiomyopathies suggesting that Titin may have multiple functions within muscle cells . However, much remains unknown about how Titin functions within cells or what its precise role(s) might be during human physiology .