Myosin head contraction

FIGURE 17.23 The mechanism of skeletal muscle contraction. The free energy of ATP hydrolysis drives a conformational change in the myosin head, resulting in net movement of the myosin heads along the actin filament. Inset) A ribbon and space-filling representation of the actin—myosin interaction. (SI myosin image courtesy of Ivan Rayment and Hazel M. Holden, University of Wiseonsin, Madison.)... 

First, in the striated muscles, the cross-sectional organization of filaments is highly ordered in a hexagonal pattern commensurate with the ratio of actin to myosin filaments and the distribution of active myosin heads, S-1 segments, helically every 60 degrees around the myosin filament. In smooth muscle, with perhaps 13 actin filaments per myosin filament, many actin filaments appear to be ranked in layers around myosin filaments. It is not known how the more distant actin filaments participate in contraction. 

When the sarcolemma is excited by a nerve impulse, the signal is transmitted into the T tubule system and a release channel in the nearby sarcoplasmic reticulum opens, releasing Ca + from the sarcoplasmic reticulum into the sarcoplasm. The concentration of Ca in the sarcoplasm rises rapidly to 10 mol/L. The Ca -binding sites on TpC in the thin filament are quickly occupied by Ca +. The TpC-4Ca + interacts with Tpl and TpT to alter their interaction with tropomyosin. Accordingly, tropomyosin moves out of the way or alters the conformation of F-actin so that the myosin head-ADP-P (Figure 49-6) can interact with F-actin to start the contraction cycle. 

Muscle contraction is a delicate dynamic balance of the attachment and detachment of myosin heads to F-actin, subject to fine regulation via the nervous system. 

When smooth muscle myosin is bound to F-actin in the absence of other muscle proteins such as tropomyosin, there is no detectable ATPase activity. This absence of activity is quite unlike the situation described for striated muscle myosin and F-actin, which has abundant ATPase activity. Smooth muscle myosin contains fight chains that prevent the binding of the myosin head to F-actin they must be phosphorylated before they allow F-actin to activate myosin ATPase. The ATPase activity then attained hydrolyzes ATP about tenfold more slowly than the corresponding activity in skeletal muscle. The phosphate on the myosin fight chains may form a chelate with the Ca bound to the tropomyosin-TpC-actin complex, leading to an increased rate of formation of cross-bridges between the myosin heads and actin. The phosphorylation of fight chains initiates the attachment-detachment contraction cycle of smooth muscle. 

Because there are many myosin heads in a thick filament, at any given moment some (probably 1% to 3%) are bound to the thin filaments. This prevents the thick filaments from slipping backward when an individual myosin head releases the actin subunit to which it was bound. The thick filament thus actively slides forward past the adjacent thin filaments. This process, coordinated among the many sarcomeres in a muscle fiber, brings about muscle contraction. 

The interaction between actin and myosin must be regulated so that contraction occurs only in response to appropriate signals from the nervous system. The regulation is mediated by a complex of two proteins, tropomyosin and troponin. Tropomyosin binds to the thin filament, blocking the attachment sites for the myosin head groups. Troponin is a Ca2+-binding protein. 

FIGURE 5-33 Molecular mechanism of muscle contraction. Conformational changes in the myosin head that are coupled to stages in the ATP hydrolytic cycle cause myosin to successively dissociate from one actin subunit, then associate with another farther along the actin filament. In this way the myosin heads slide along the thin filaments, drawing the thick filament array into the thin filament array (see Fig. 5-32). 

Other major differences between kinesins and myosin II heads involve kinetics180 181 and processivity.173 Dimeric kinesin is a processive molecule. It moves rapidly along microtubules in 8-nm steps but remains attached.182 1823 Myosins V and VI are also proces-sive1 83, a3e but myosin II is not. It binds, pulls on actin, and then releases it. The many myosin heads interacting with each actin filament accomplish muscle contraction with a high velocity in spite of the short time of attachment. Ned and Kar3 are also nonprocessive and slower than the plus end-oriented kinesins.184... 

Steps in the contraction process. Because contraction is a cyclical process, the choice of a starting point is somewhat arbitrary. Five frames are shown the first two and the last two frames are identical to make the cyclical nature of the process clear. In the first frame (a), the myosin head groups contain the hydrolysis products of a single ATP molecule, ADP and P . A structural transition in the actin leads to contact between the actin and the myosin and the release of P,. 

In the second frame (b), strong bridges form between actin and myosin. This is followed by a structural alteration in the myosin molecules and an effective translocation of the thick filament relative to the thin filament in (c). During this process the ADP is released. After the translocation step, the bridge structure is broken by the binding of ATP, which is rapidly hydrolyzed to ADP and Pj. Each thick filament has about 500 myosin heads, and each head cycles about five times per second in the course of a rapid contraction. 

One of the tasks of structural biologists studying muscle contraction is to determine the organization and shapes of the myosin head in muscle under different physiological conditions. The technique of low-angle X-ray diffraction has unique advantages in this process, particularly since it can be applied to living muscle, which can be stimulated to produce active force or can be studied under a variety of different steady-state conditions. The main problem with X-ray fiber diffraction, as detailed in Squire and... 

Dobbie, I., Linari, M., Piazzesi, G., Reconditi, M., Koubassova, N., Ferenczi, M. A., Lombardi, V., and Irving, M. (1998). Elastic bending and active tilting of myosin heads during muscle contraction. Nature 396, 383-387. 

Harford, J. J., Chew, M. W., Squire, J. M., and Towns-Andrews, E. (1991). Crossbridge states in isometrically contracting fish muscle Evidence for swinging of myosin heads on actin. Adv. Biophys. 27, 45-61. 

Juanhuix, J., Bordas, J., Campmany, J., Svensson, A., Bassford, M. L., and Narayan, T. (2001). Axial disposition of myosin heads in isometrically-contracting muscles. Biophys.J. 80, 1429-1441. 

Martin-Femandez, M. L., Bordas, J., Diakun, G., Harries, J., Lowy, J., Mant, G. R., Svennson, A., and Towns-Andrews, E. (1994). Time-resolved X-ray diffraction studies of myosin head movements in live frog sartorius muscle during isometric and isotonic contractions./. Mus. Res. CellMotil. 15, 319-348. 

Yagi, N. (1996). Labelling of thin filaments by myosin heads in contracting and rigor vertebrate skeletal muscles. Acta Cryst. D. 52, 1169-1173. 

Figure 5.16. Summary of contraction cycle. Interaction between myosin head and F-actin involves the binding of ATP to a cleft in the myosin head (top) that associates myosin head from actin, causing hydrolysis of ATP into ADP. This is followed by binding of myosin head to actin, loss of y-phosphate, and then loss of ADP and repeat of the cycle (see Silver and Christiansen, 1999).

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