Group:MUZIC:Titin

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Revision as of 21:38, 19 July 2011

Titin

The giant protein titin (also called „connectin“ by Maruyama et al., 1977) is the largest known protein composed of 38138 amino acid residues. The human titin gene is located on chromosome 2q31, is 294 kilobases large and contains 363 exons. Its molecular weight varies from 1,5 megaDalton to ~3,7 MegaDalton in different isoforms. These isoforms aree produced by alternative splicing mostly in the I-band region of titin. Titin is third most abundant protein in striated muscle cells after actin and myosin. It forms so called “third filament system”. Single titin macromolecules have length >1-μm and span from Z-disc to M-line through half-sarcomere. The main function of titin is to provide passive tension which helps to restore the length of resting sarcomere after contractile activity. However, titin has other important functions: it acts as a molecular ruler, determining correct location of other muscular proteins. Titin also serves as a nodal point in signaling cascades within sarcomere, takes part in sarcomere formation and maintenance. It is also worth mentioning that set of titin-like proteins is expressed in non-muscular tissues and a distinct titin isoform of ~1 MDa can be found in human smooth muscle tissues (280 of 363 existing exons are not included). 90 % of titin is represented by immunoglobulin (Ig) or fibronectin-type-III (FN3)-like domains ^[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 is composed of a number of immunoglobulin-type domains and a moiety of unique 45-residue repeats called Z-repeats. 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. 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. α-actinin interacts with titin in region of above-mentioned repeats ^[2]. 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: