Sandbox GGC5

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Function

Titin is a key component in the assembly and function of vertebrate striated muscles. Titin provides connections at the level of individual micro-filaments and contributes to the fine balance of forces between the two halves of the sarcomere. In non-muscle cells, titin plays a role in chromosome condensation and chromosome segregation during mitosis.

On the cellular level, titin is typically located within the nucleus of the cell; however, it can also be located within the cytoplasm.

Disease

Myopathy, myofibrillar, 9, with early respiratory failure:

This disease is characterized by adult onset of weakness in proximal, distal, axial and respiratory muscles. The main symptoms of onset are pelvic girdle and neck weakness. Ultimately, the weakness will affect the proximal compartment of both the upper and lower limbs. Additional symptoms include varying degrees of Achilles tendon contractures, spinal rigidity and muscle hypertrophy. In extreme cases, respiratory involvement will often lead to the requirement for non-invasive treatment. The natural variant indicating this disease can be found at position 279 and it disrupts NBR1-binding.

Cardiomyopathy, familial hypertrophic 9:

This disease is a hereditary heart disorder characterized by ventricular hypertrophy. The hypertrophy is usually asymmetrical and often involves the interventricular septum. The symptoms of this disease include: difficult/labored breathing, fainting, collapse, palpitations and chest pains. These symptoms are readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death. This disease is characterized by a variant in position 740.

Cardiomyopathy, dilated 1G:

This disorder is characterized by ventricular dilation and impaired systolic function. This disorder results in congestive heart failure and arrhythmia, ultimately leading to a high possibility of premature death. This disease is often indicated by natural variants in the following locations: 54, 743, 976, 3799, 4465 or 32996. All of these variants affect the interaction with the TCAP/telethonin.

Tardive tibial muscular dystrophy:

This disease is a late-onset, autosomal dominant distal myopathy. Symptoms are typically muscle weakness and atrophy that are typically confined to the anterior compartment of the lower leg. Clinical onset of this disease usually occur at 35 to 45 years or later. The natural variant of this disease occurs at positions 34306 and 34315.

Muscular dystrophy, limb-girdle, autosomal recessive 10:

Relevance

Structural highlights

•This is the version of the titin molecule. This structure is colored to differentiate each chain, starting with the blue 5' amino end, ending with the red 3' carboxyl end.

•This secondary structure of titin highlights the sections of the titin molecule. In this representation, Polar sections of titin are shaded in purple and hydrophobic regions are shaded in grey. The central beta-sandwich structure of the molecule encloses a well defined hydrophobic core. This helps to stabilize the molecule that contains no disulfide bridges and rely solely on hydrogen bonding in the side chains and backbone.

•This alternate structure highlights the involved in activity regulation. Full activation of the protein kinase domain requires both phosphorylation of Tyrosine to prevent it from blocking the catalytic aspartate residue, and binding of the C-terminal regulatory tail of the molecule which results in ATP binding to the kinase.

•This is the structure. This secondary view shows multiple titin proteins connected together. This representation is known as the titin band.