This energy is expended as the myosin head moves through the power stroke; at the end of the power stroke, the myosin head is in a low-energy position. After the power stroke, ADP is released; however, the cross-bridge formed is still in place, and actin and myosin are bound together. ATP can then attach to myosin, which allows the cross-bridge cycle to start again and further muscle contraction can occur Figure 1. The movement of the myosin head back to its original position is called the recovery stroke.
Resting muscles store energy from ATP in the myosin heads while they wait for another contraction. Figure 1. With each contraction cycle, actin moves relative to myosin. When a muscle is in a resting state, actin and myosin are separated.
To keep actin from binding to the active site on myosin, regulatory proteins block the molecular binding sites. Tropomyosin blocks myosin binding sites on actin molecules, preventing cross-bridge formation and preventing contraction in a muscle without nervous input. Troponin binds to tropomyosin and helps to position it on the actin molecule; it also binds calcium ions. To enable a muscle contraction, tropomyosin must change conformation, uncovering the myosin-binding site on an actin molecule and allowing cross-bridge formation.
This can only happen in the presence of calcium, which is kept at extremely low concentrations in the sarcoplasm. Domain 1 is subdivided into subdomains 1 and 2 , and domain 2 is subdivided into subdomains 3 and 4. At the bottom of cleft are two residues that are important to ATP hydrolysis and therefore to microfilament dynamics.
Peering into the cleft, it can be seen that histidine from subdomain 3 and glutamine from subdomain 1 are involved in positioning a key water oxygen blinking for a nucleophilic attack of the gamma phosphate blinking of ATP. A magnesium ion is involved in stabilizing the terminal phosphates of ATP as catalysis proceeds. Note that the nucleotide contacts all 4 subdomains. ATP hydrolysis can thus change the conformation of the actin monomer. A simulation of the folding changes induced by ATP hydrolysis is shown at left.
Although the starting and ending structures are genuine models based on crystallographic data PDB ID's 1YAG and 1J6Z , the intermediate transitions are based on linear interpolation and some energy minimization and are only possible structures. This simulation was generated using the Yale Morph Server at the Database of Macromolecular Movements , maintained by the Gerstein lab. A model of F-actin has been produced by fitting different crystal structures of G-actin both ATP and ADP-bound forms into an atomic density map derived from cryo-electronmicroscopic examination of F-actin bundles from the acrosomal reaction of horseshoe crab Limulus sperm.
The microfilament consists of a helical arrangement of two actin strands formed by polymerization of G-actin monomers. The twist of the helix can be influenced by the cellular environment, including actin binding proteins. Actin filaments are key components of the sarcomeres, the fundamental units of muscle contraction. At this point it is recommended that you consult a textbook to review the molecular architecture of muscle myofibrils and sarcomeres and the mechanism of calcium release from intracellular stores in muscle cells in response to neuronal stimulation.
Thin filaments in the sarcomere, comprising F-actin, tropomyosin, and troponin proteins, are the substrate upon which the myosin molecules of the thick filaments exert their pull, thus transducing the chemical energy of ATP hydrolysis into a mechanical force that contracts individual myofibrils within muscle cells.
A length of F-actin in a thin filament is shown at left. The orientation of the helical filament is such that the Z-line is to the right and the M-line is to the left in the sarcomere. Two tropomyosin molecules are wound around the actin polymer. Troponin protein complexes are associated with each tropomyosin molecule , separated by the approximate length of tropomyosin, approximately Each troponin complex is a heterotrimer that contains one troponin C , one troponin T , and one troponin I component.
Each troponin C from skeletal muscle can bind 4 calcium ions via 4 EF-hand domains. We can now consider the structural regulation of thin filament structure in skeletal muscle in response to an action potential.
This exposes sites on actin monomers in the filament that can be bound by the molecular motor, myosin, the major protein of the thick filaments within the sarcomere.
Myosin II is the motor protein of the sarcomeric thick filament that transduces the chemical energy of ATP hydrolysis and release of ADP and Pi into mechanical energy that drastically alters the conformation of the protein. This allows myosin to undergo repeated cycles of actin binding and release the actomyosin cycle. The conformational movements of portions of myosin are amplified to produce the mechanical force that drives the sliding of thin filaments, thus shortening the sarcomere and causing muscle contraction.
Myosin II structure and its interaction with actin will be considered in the remaining part of this tutorial. Before embarking on the role of myosin II conformational changes in the actomyosin cycle, it is highly recommended that you familiarize yourself with this cycle as described in a texbook.
Briefly summarized, the cycle involves 4 steps:. Each myosin molecule in the thick filament is composed of two myosin heavy chains and two pairs of light chains for reference, see Figure 1.
The heavy chain motor domain plus lever arm is referred to as subfragment 1 S1 of myosin II. The S1 subfragment shown is from myosin II of striated muscle of a vertebrate chicken.
The extended tail of the myosin molecule, which forms a coiled-coil with another myosin II heavy chain, is not shown. The myosin II light chains , are tandemly bound to the heavy chain lever arm. The regulatory light chain and the essential light chain serve regulatory roles and can also stabilize the lever as well as provide for association of dimerized heavy chains with other myosin II molecules in the thick filament.
This is promoted by phosphorylation of the light chains by myosin light chain kinase MLCK or Rho-associated kinases. Both light chains show structural homology with calmodulin. Turning now to the structure of the heavy chain motor domain , four major subdomains plus several elements that articulate movements between the subdomains and between the motor domain and the lever have been described.
Sherman, and Dorothy Luciano. Human Physiology. The Mechanisms of Body Function. McGraw Hill. Click image. Click image for animation.
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