Muscle structure troponin

Herzberg, O., James, M.N.G. Structure of the calcium regulatory muscle protein troponin-C at 2.8 A resolution. Nature 313 653-659, 1985. 

In addition to the major proteins of striated muscle (myosin, actin, tropomyosin, and the troponins), numerous other proteins play important roles in the maintenance of muscle structure and the regulation of muscle contraction. Myosin and actin together account for 65% of the total muscle protein, and tropomyosin and the troponins each contribute an additional 5% (Table 17.1). The other regulatory and structural proteins thus comprise approximately 25% of the myofibrillar protein. The regulatory proteins can be classified as either myosin-associated proteins or actin-associated proteins. 

A molecular view of muscle structure, (a) Segment of actin-tropomyosin-troponin. 

The Ca2+-binding subunit TN-C is homologous to calmodulin with four EF-hands. In contrast to calmodulin, which is ubiquitously expressed in multicellular eukaryotic organisms and interacts with many targets, troponin specifically regulates muscle contraction. There are some structural differences between Troponin C in skeletal and cardiac muscles reflecting their physiological differences. 

The superstructure of smooth muscle actin filaments is differentiated from those of striated muscle by the absence of the troponins and the lateral organization by association of the filaments with dense bodies instead of with the Z-line. How these differences are encoded is again not at all clear. However, the myofibrillar structure and the alignment of the alternating actin and myosin filaments is apparently due primarily to dense bodies and the actin-actinin macrostructures. As the bent dumbbell shaped actins assemble into filaments they are all oriented in the same direction. The S-1 fragments of myosin will bind to actin filaments in vitro and in... 

In striated muscle, there are two other proteins that are minor in terms of their mass but important in terms of their function. Tropomyosin is a fibrous molecule that consists of two chains, alpha and beta, that attach to F-actin in the groove between its filaments (Figure 49-3). Tropomyosin is present in all muscular and muscle-fike structures. The troponin complex is unique to striated muscle and consists of three polypeptides. Troponin T (TpT) binds to tropomyosin as well as to the other two troponin components. Troponin I (Tpl) inhibits the F-actin-myosin interaction and also binds to the other components of troponin. Troponin C (TpC) is a calcium-binding polypeptide that is structurally and functionally analogous to calmodulin, an important calcium-binding protein widely distributed in nature. Four molecules of calcium ion are bound per molecule of troponin C or calmodulin, and both molecules have a molecular mass of 17 kDa. 

Smooth muscles have molecular structures similar to those in striated muscle, but the sarcomeres are not aligned so as to generate the striated appearance. Smooth muscles contain a-actinin and tropomyosin molecules, as do skeletal muscles. They do not have the troponin system, and the fight chains of smooth muscle myosin molecules differ from those of striated muscle myosin. Regulation of smooth muscle contraction is myosin-based, unlike striated muscle, which is actin-based. However, like striated muscle, smooth muscle contraction is regulated by Ca. ... 

Upon entering the smooth muscle cell, Ca++ ions bind with calmodulin, an intracellular protein with a chemical structure similar to that of troponin. The resulting Ca++-calmodulin complex binds to and activates myosin kinase. This activated enzyme then phosphorylates myosin. Crossbridge cycling in smooth muscle may take place only when myosin has been phosphorylated. 

Zot, A. S. and Potter, J. D. Structural aspects of troponin-tropomyosin regulation of skeletal muscle contraction. Annu. Rev. Biophys. Biophys. Chem. 16 535-560,1987. 

Magnesium is also of interest as a replacement for Ca(ll) in calcium-requiring enzymes. In some of these, the replacement is simple (Lewinski and Lebioda, 1986), and in others it cannot occur. NMR studies show that magnesium can bind in the calcium sites of troponin C (Tsuda et al., 1990). The structure of turkey skeletal muscle troponin C has recently been reported (Herzberg and James, 1985). In one domain the replacement of Ca(II) by Mg(II) causes a conformational change, but in the other domain it does not. 

Parvalbumin is another protein in search of a function. It contains three HLH motifs (Mr 1 IK), but only the second and third are functional Ca " -binding sites. These are high-affinity Ca /Mg sites, and both are filled with Ca in the known crystal structures (references in Table I). In fast twitch muscle, where most parvalbumins are found, the protein is postulated to act as a Ca " buffer (Haich a/., 1979 Gi s etal., 1982). As Ca is released from troponin C after muscle contraction, the Ca may be bound by parvalbumin to prevent reinitiation of contraction. In resting cells parvalbumin likely binds Mg ", rather than Ca (Haiech etal., 1979). 

Troponin C in muscle is structurally closely related to catmodulin. It has 4 EF structures, of which only two can be occupied by Ca. Troponin C is a component of the contraction apparatus of muscle. Ca binding to troponin C induces a conformational change in the troponin complex that leads to contraction of muscle. 

In summary, it may be that binding of calcium (or magnesium) to the Ca2+-Mg2+ sites controls and stabilizes the structure of troponin c,245,246 and that the binding of calcium to the calcium-specific sites causes more localized structural changes which serve to trigger muscle contraction. 

Protein sequence and structure of troponin (TN-C) and carp muscle calcium binding parvalbumin (MCBP) are known199-201). MCBP has two calcium binding regions each consisting of an a-helix, a loop about the calcium ion and another a-helix, as so-called EF hand (Fig. 21)202,203). 

The calcium binding component of troponin from rabbit muscle contains four homologous EF hands. It was proposed that the structure of TN—C is rhombic and consists of two pairs of EF hands in approximate point group symmetry (space group 222). 

Collins, J. H., Potter, J. D., Horn, M. J., Wilshire, G., and Jackman, N. Structural studies on rabbit skeletal muscle troponin C Evidence for gene replication and homology with calcium binding proteins from carp and hake muscle. In calcium binding proteins (eds. 

Li, Y., Mui, S., Brown, J. H., Strand, J., Reshetnikova, L., Tobacman, L. S., and Cohen, C. (2002). The crystal structure of the C-terminal fragment of striated-muscle a-tropomyosin reveals a key troponin T recognition site. Proc. Natl. Acad. Sci. 99, 7378-7383. 

Figure 10-4. The structure of the calciumbinding protein troponin from chicken skeletal muscle. Although this is an exceptionally complicated ligand to a coordination chemist, the binding of calcium ions is to the hard donor sites that might be predicted. Binding of the calcium triggers a conformational change.

Brown, J. H., and Cohen, C. (2005). Regulation of muscle contraction by tropomyosin and troponin How structure illuminates function. Adv. Protein Chem. 71, 121-159. 

The muscle sarcomere contains the principal contractile proteins myosin and actin (Fig. 3A to C), which on their own can produce force and movement, together with a number of cytoskeletal and regulatory proteins. The latter include titin, C-protein (MyBP-C), tropomyosin, troponin, a-actinin, myomesin, M-protein, and so on. Some of these help to organize the myosin and actin filaments in the sarcomere, some to define the filament lengths and structure, some to regulate activity, and some to modulate the actin-myosin interaction when the muscle is active. 

Herzberg, O., and James, M. N. (1988). Refined crystal structure of troponin C from turkey skeletal muscle at 2.0 A resolution./ Mol. Biol. 203, 761-779. 

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