Actin tropomyosin role

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. 

Lehrer, S. S., Golitsina, N. L., and Geeves, M. A. (1997). Actin-tropomyosin activation of myosin subfragment 1 ATPase and thin filament cooperativity. The role of tropomyosin flexibility and end-to-end interactions. Biochemistry 36, 13449-13454. 

In vitro experimentation has shown that caldesmon is an integral component of smooth muscle thin filaments and plays a central role in their Ca2+-dependent regulation. A mechanism analogous to that of troponin has been proposed this now requires extensive testing. The structure of the regulatory domain of caldesmon is not well defined and we look forward to being able to describe this in three dimensions and in combination with its physiological partners actin, tropomyosin, and calmodulin. 

To account for activation of arterial smooth muscle independently of LC20 phosphorylation, attention has been focused on the possible roles of the thin filament-associated regulatory proteins, caldesmon and calponin. Both proteins have been localized in the actomyosin domain of the smooth muscle cell and both have been shown to inhibit actin-activated myosin ATPase by interacting with F-actin, tropomyosin, and/or myosin (Clark et al., 1986 Takahashi et al.,... 

Calponin [119] and caldesmon [120] are two thin filament associated proteins that bind to F-actin, tropomyosin and calmodulin. Interaction of 34 kDa calponin with F-actin and tropomyosin takes place in a Ca +-inde-pendent manner, whereas that with calmodulin is regulated in a Ca -de-pendent manner. The key role of calponin and caldesmon in SM is to down-regulate actomyosin ATPase activity in vitro [120,121]. Thus, they may participate in regulation of contractile performance. Despite their apparent functional similarity, sequence analysis indicates that calponin and caldesmon are not related proteins. They act by different mechanisms... 

Proteins can be broadly classified into fibrous and globular. Many fibrous proteins serve a stmctural role (11). CC-Keratin has been described. Fibroin, the primary protein in silk, has -sheets packed one on top of another. CoUagen, found in connective tissue, has a triple-hehcal stmcture. Other fibrous proteins have a motile function. Skeletal muscle fibers are made up of thick filaments consisting of the protein myosin, and thin filaments consisting of actin, troponin, and tropomyosin. Muscle contraction is achieved when these filaments sHde past each other. Microtubules and flagellin are proteins responsible for the motion of ciUa and bacterial dageUa. 

Tropomyosin is thought to lie in the groove formed between the associated actin strands. The sites at which the myosin crossbridges attach are affected by the relationship between tropomyosin and the actin strands. The role of tropomyosin in smooth muscle is completely undefined while in striated muscle it is clearly involved in the activation of contraction. The difference is made clear by the absence from smooth muscle of the protein, troponin, which in striated muscle provides the binding site for the triggering calcium. 

The general picture of muscle contraction in the heart resembles that of skeletal muscle. Cardiac muscle, like skeletal muscle, is striated and uses the actin-myosin-tropomyosin-troponin system described above. Unlike skeletal muscle, cardiac muscle exhibits intrinsic rhyth-micity, and individual myocytes communicate with each other because of its syncytial nature. The T tubular system is more developed in cardiac muscle, whereas the sarcoplasmic reticulum is less extensive and consequently the intracellular supply of Ca for contraction is less. Cardiac muscle thus relies on extracellular Ca for contraction if isolated cardiac muscle is deprived of Ca, it ceases to beat within approximately 1 minute, whereas skeletal muscle can continue to contract without an extraceUular source of Ca +. Cyclic AMP plays a more prominent role in cardiac than in skeletal muscle. It modulates intracellular levels of Ca through the activation of protein kinases these enzymes phosphorylate various transport proteins in the sarcolemma and sarcoplasmic reticulum and also in the troponin-tropomyosin regulatory complex, affecting intracellular levels of Ca or responses to it. There is a rough correlation between the phosphorylation of Tpl and the increased contraction of cardiac muscle induced by catecholamines. This may account for the inotropic effects (increased contractility) of P-adrenergic compounds on the heart. Some differences among skeletal, cardiac, and smooth muscle are summarized in... 

In skeletal muscle, calcium binds to troponin and causes the repositioning of tropomyosin. As a result, the myosin-binding sites on the actin become uncovered and crossbridge cycling takes place. Although an increase in cytosolic calcium is also needed in smooth muscle, its role in the mechanism of contraction is very different. Three major steps are involved in smooth muscle contraction ... 

In addition to actin and myosin, other proteins are found in the two sets of filaments. Tropomyosin and a complex of three subunits collectively called troponin are present in the thin filaments and play an important role in the regulation of muscle contraction. Although the proteins constituting the M and the Z bands have not been fully characterized, they include a-actinin and desmin as well as the enzyme creatine kinase, together with other proteins. A continuous elastic network of proteins, such as connectin, surround the actin and myosin filaments, providing muscle with a parallel passive elastic element. Actin forms the backbone of the thin filaments [4]. The thin... 

In smooth muscle, caldesmon plays an analogous role to that of troponin in striated muscle in that it blocks the myosin binding sites. The CaCM complex removes caldesmon from its binding on the thin actin filaments allowing tropomyosin to reposition in the helical grooves of F-actin leading to myosin ATP ase activation. 

You may be asked to draw a diagram of the sarcomere. It is made up of actin and myosin filaments, as shown below. The thick myosin filaments contain many crossbridges, which, when activated, bind to the thin actin filaments. Tropomyosin molecules (containing troponin) run alongside the actin filaments and play an important role in excitation-contraction coupling. 

Tropomyosin is a long helical molecule (70 kDa) which extends along the long axis of the actin filament (Figure 13.7). Each tropomyosin molecule covers seven actin monomers and plays a central role in the regulation of muscle contraction. 

Fibrous proteins represent a substantial subset of the human proteome. They include the filamentous structures found in animal hair that act as a protective and thermoregulatory outer material. They are responsible for specifying much of an animal s skeleton, and connective tissues such as tendon, skin, bone, cornea and cartilage all play an important role in this regard. Fibrous proteins are frequently crucial in locomotion and are epitomised by the muscle proteins myosin and tropomyosin and by elastic structures like titin. Yet again the fibrous proteins include filamentous assemblies, such as actin filaments and microtubules, where these provide supporting structures and tracks for the action of a variety of molecular motors. 

Troponin s role in the thin filament of vertebrate striated muscles is primarily that of regulation. The three subunits of this complex form what has been described as a Ca2+-sensitive latch that fixes tropomyosin s position on the actin helix in the off state of contraction (Lehman et al., 2001). One subunit of the complex, troponin T (TnT), maintains an invariant linkage to tropomyosin, and another, troponin I (Tnl), a variable linkage to actin. The third subunit, troponin (TnC) is the Ca2+sensor of the complex and indeed of the myofibril itself. The latch is opened or closed depending on the level of Ca2+. Correspondingly, a series of conformational changes takes place in the entire complex and in the thin... 

The seven distinct amino acid positions and associated interactions that are produced from the a-helical coiled-coil provide the basic structural unit of tropomyosin. These elements superimpose on the longer, roughly 40-residue, functional unit of tropomyosin (see Fig. 1), and patterns of residues found both in the core of the coiled-coil as well as on its surface are repeated seven times in a full-length tropomyosin molecule and play a role in the periodic binding of tropomyosin to actin. 

Analyses of the tropomyosin sequence have shown long-range periodicities of certain surface acidic and apolar residues that are likely to be recognition sites for actin. These features are discussed below in relation to their role in regulation (see Turning on the Thin Filament section). 

Actin and tubulin are two important cellular components that are involved in cell shape and movement. Actin is present in all mammalian cells and is involved in cellular transport and phagocytosis (eating of extracellular materials), provides rigidity to cell membranes, and when bonded to tropomyosin and troponin, forms the thin filaments of muscle. Thbulin is the subunit from which microtubules are self-assembled. Microtubules are most commonly known for their role in cell division. The mechanisms of self-assembly of these macromolecules have been well studied and are important models of biological assembly processes. Below we examine each of these processes. 

See also The Structure of Muscle, Tropomyosin, Actin and Myosin, The Sliding Filament Model, The Role of Calcium in Contraction... 

---