Group:MUZIC:Titin

Evidence for a dimeric assembly of two titin/telethonin complexes induced by the telethonin C-terminus. PMID 16713295 </ref>' scene='User:Victor_Deineko/Workbench/titin/Complex_of_titin-telethonin/1' />

Z-disc fragment of titin

Approximately 2000 residues part of titin’s amino-terminus, coded by exons 1–28, is localized within Z-disc. It consists of immunoglobulin-type domains and a variable number of unique 45-residue motifs called Z-repeats ^[7] These repeats are located between Ig-domains 2 and 3. Immunoglobulin domains Z1-Z4 are present in all isoforms of titin, whereas number of Z-repeats varies from 2 to 7 in different types of striated muscles due to differential splicing. Both repeats 1 and 7 are present in all isoforms except smooth muscle titin. At the N-terminal end of titin Ig-domains Z1/Z2 interact with telethonin (also called “T-Cap”) which connects titin molecules from same half of the sarcomere into antiparallel “sandwich”. Due to numerous hydrogen bonds which connect β-strands of two molecules titin-telethonin complex is extremely resistant to stretching. Telethonin is proved to be responsible for anchoring of titin molecules in Z-disc. It also plays a role of mechanosensor and helps to target other sarcomeric proteins (for example, FATZ, MLP, minK, PKD, MURF1 ) .Domains Z1/Z2 are known to be connected to small-ankyrin-1 which is associated with spectrin, desmin and obscurin. Interaction with actin is reported for domains Z9-I1. Ig-like domains Z8/Z9 are bound to obscurin. Other proven partners inside Z-disk are nebulin and filamin C, that both interact with titin by their C-terminal parts. Interaction of α-actinin and Z-repeats of titin within Z-disc was shown experimentally more than a decade ago ^{[8] [9] [10]}. Binding was reported for Z-repeats 1 and 7 and calmodulin-like domains (syn. EF-hands) at C-terminus of α-actinin. Third putative point of interaction is located between Z-repeat 7 and Ig-domain Z3 of titin and is contacting spectrin-like domains of α-actinin homodimer. Strong interactions between actin, α-actinin and titin form a spatial scaffold inside Z-disc, enabling correct placement of other protein components. Z-disc connects all elastic and contractile components of sarcomere and enables transduction of tensile forces. some of these components take part in different signaling pathways, others are responsible for direct mechanosensing. Thickness of Z-discs varies significantly between different types of muscles due to adaptation to different levels of mechanic stress. A hypothesis that ascribes titin, particularly it’s Z-repeats, role of the Z-disc thickness determinant, was proposed. It was grounded on the fact that number of repeats and layers in Z-disc correlate ( i.e. sarcomeres with full range of Z-repeats have the thickest disc). However, given idea remains unproven, since it has been found that length of a single repeat is less that thickness of single layer inside Z-disc (19 nm) and thus periodicity cannot be directly determined in proposed way. Number of titin’s point mutations that are related to myopaties is known. Some examples of such mutations together with their effect are listed below. Val54Met point mutation in domain Z1 leads to decreased binding to telethonin. Z-repeat 7 Ala743Val point mutation affects interaction with α-actinin. Point mutation of Ala740 to Leu has opposite effect. Missense mutation in Z4 (Trp930 to Arg) is predicted to destroy Ig-domain fold.

Functions

Titin acts as the tension sensor in muscle cells. As it was mentioned before, titin molecules are extended within sarcomere, thus, have a proper position for detecting the sarcomere’s contraction and transfering correponding signals. N-termins of titin is attached to the actin filaments at the Z-disk and connected to myosin in the A-band/M-band. Given parts of titin sense tensile forces generated by sarcomere during stretch/contraction. Transmission of these signals is possible because of titin’s interactions with other sarcomeric proteins. Up to date approximately 20 different proteins are known to interact with titin at so called “hot spots” along the entire molecule and to participate in signal transduction.

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Structures

References: