Within eukaryotic cells, numerous essential processes are constantly occurring, keeping the cell active and functional. From cell division to the organized movement of cellular organelles and other components, and even our muscle contraction—all these dynamic tasks are driven by the coordinated activity of specific proteins. Among the primary and indispensable of these is Myosin. Myosin is a type of Motor Protein that can move along the Actin filaments, which are a component of the cell's cytoskeleton. This movement is made possible by converting chemical energy obtained from the Adenosine Triphosphate (ATP) molecule into mechanical energy. This ATP-dependent motility of Myosin in living systems forms a fundamental basis for cellular functionality. In this detailed discussion, we will delve deeply into the complex structure of Myosin protein, its various species or types, and its multifaceted roles in living cells, especially focusing on the core process of muscle contraction, the Cross-Bridge Cycle.

Basic Structure and Functional Domains of Myosin

To understand the function of Myosin protein, it is essential to have an idea of its three-dimensional structure. Most Myosin proteins are composed of polypeptide chains called Heavy Chains and Light Chains. These chains assemble in a specific manner to form the functional Myosin molecule. For convenience in structure and function, the main parts of Myosin are divided into three functional domains:

  • Head Domain: This is the most important and active part of Myosin, where its core activities take place. The Head Domain has two main functional sites:
    • Actin Binding Site: Through this site, the Myosin Head binds to the Actin filament. A proper and specific bond with Actin is essential for Myosin's movement.
    • ATP Binding Site: The ATP molecule binds to this site. The binding, hydrolysis, and release of ATP and its products (ADP and Pi) cause conformational changes in the Myosin Head, which control its movement on Actin. The Head Domain is the site where ATP hydrolysis occurs, converting chemical energy into kinetic energy. It acts as an ATPase enzyme.

    In summary, the Head Domain is the driving force of Myosin, interacting with Actin and generating and using energy to create movement.

  • Neck Domain: The Neck Domain is located immediately after the Head Domain. It is a relatively rigid part and typically has Light Chains (such as Essential Light Chain or ELC and Regulatory Light Chain or RLC) attached to it. These Light Chains increase the rigidity of the neck and help regulate the movement of the Head Domain. The Neck Domain acts as a Lever Arm. When ATP hydrolysis causes conformational changes in the Head Domain, this Lever Arm effectively converts the force applied by the head on Actin into a displacement, much like a handle. The length of the neck influences the amount of displacement during the Power Stroke.
  • Tail Domain: The Tail Domain is the long, rear part of Myosin connected to the Neck Domain. The structure of the Tail Domain shows the greatest variation among different Myosin species or Isoforms. The specific structure of this Tail Domain determines what function Myosin will perform within the cell and how it will associate with other cellular components, such as other Myosin molecules, cellular organelles, or the cell membrane.
    • The Tail Domains of some Myosins (like Myosin II) can assemble to form long filaments. This filament formation is essential for collective work like muscle contraction or Cytokinesis.
    • The Tail Domains of other Myosins (like Myosin V) contain specialized binding sites for associating with specific cargoes (like organelles or Vesicles) or specific cellular structures.

Thus, the head is the center of activity, the neck is the lever arm that converts that activity into motion, and the tail is the part that keeps Myosin engaged in its specific task and determines what it carries.

Diversity of the Myosin Family: Classical and Unconventional Myosins

In eukaryotic organisms, including humans, Myosin does not exist in just one form but is a member of a large and diverse family. Based on their structure, mode of movement, and functions, the Myosin family is primarily divided into two large groups: Classical Myosins and Unconventional Myosins.

Classical Myosin: Type II Myosin (Myosin II)

Type II Myosin is the most well-known and widely discussed member of the Myosin family. It is found in abundance primarily in Muscle Cells, where it performs the main function of muscle contraction. However, it is also present in small amounts in almost all eukaryotic cells and plays a role in cell division during the final stage (Cytokinesis).

  • Structure: Type II Myosin is a Dimer, meaning it is composed of two Heavy Chains. Each Heavy Chain has one head and a long tail. These tail regions twist around each other in a helical manner to form a Coiled-Coil structure. Light Chains are attached to the Neck Domain.
  • Filament Formation: A unique characteristic is the ability of the Tail Domain of Type II Myosin to assemble into well-organized and large Myosin Filaments, known as Thick Filaments in muscle cells. These Thick Filaments are located between the Thin Filaments composed of Actin.
  • Functionality: The main function of Type II Myosin is to pull the Actin filaments towards the center of the Thick Filament. This relative sliding of Thin and Thick Filaments causes muscle contraction, which is explained by the Sliding Filament Model. Type II Myosin generally moves towards the negative end of the Actin filament.

Unconventional Myosins:

All other members of the Myosin family, besides Classical Type II Myosin, are called Unconventional Myosins. Their structure and function are different from Type II. Their main characteristic is that they generally do not form filaments, and their Tail Domains are specialized for binding to various types of cargo (cellular components) or cellular structures. Some notable examples of Unconventional Myosins include:

  • Type I Myosin (Myosin I): These are typically Monomers, meaning they consist of only one Heavy Chain. Their Tail Domain is often associated with the cell membrane, and they play roles in Endocytosis, organization of the Actin cytoskeleton, and regulation of cell membrane tension.
  • Type V Myosin (Myosin V): This is a Dimer, but its tail is different from Type II and contains a cargo-binding domain. Type V Myosin plays a major role in the intracellular transport of Organelles (such as mitochondria, vesicles originating from the Golgi apparatus) and other large molecules (mRNA). Their mode of movement is like "walking step-by-step" (Processive or Hand-over-Hand Walking), allowing them to travel long distances along Actin filaments.
  • Type VI Myosin (Myosin VI): This is the only Myosin that typically moves in the opposite direction (towards the positive end) along Actin filaments compared to other Myosins. It is important in Endocytosis, transport of Vesicles from the Golgi apparatus, and regulation of specific cellular adherence.

Additionally, many other classes of Myosin (such as Myosin VII, X, XV, etc.) have been discovered, each with their own specific cellular functions, such as in hearing, vision, and balance, and Cell Polarization, etc. The immense diversity of the Myosin family demonstrates its indispensability for the complex functions of living cells.

Molecular Mechanism of Muscle Contraction: The Cross-Bridge Cycle

The main driving force of muscle contraction is the cyclical interaction between Actin and Type II Myosin filaments, known as the Cross-Bridge Cycle. This process is accomplished using energy obtained from the ATP molecule. In each cycle, a Myosin Head binds to the Actin filament, uses ATP energy to pull the Actin, and then detaches to prepare for a new binding site on Actin. Millions of Myosin Heads repeat this cycle simultaneously but independently. The steps of the Cross-Bridge Cycle are described in detail below:

  1. ATP Binding and Dissociation of Myosin from Actin: This step marks the beginning of the cycle or the end of the previous cycle. When an ATP (Adenosine Triphosphate) molecule binds to the specific ATP-binding site of the Myosin Head, an immediate conformational change occurs in the Myosin Head. As a result of this change, the affinity of the Myosin Head for the Actin filament is greatly reduced. Consequently, the Myosin Head dissociates from the Actin filament. This dissociation is essential for muscle relaxation and subsequent contraction. The presence of ATP plays a key role in this step. In the absence of ATP, Myosin remains tightly bound to Actin, which is the cause of rigor mortis.
  2. ATP Hydrolysis and Cocking of the Myosin Head: After dissociating from Actin, the Myosin Head hydrolyzes the bound ATP molecule. This process is called Hydrolysis, where the ATP molecule is converted into ADP (Adenosine Diphosphate) and an Inorganic Phosphate (Pi). The energy released from this hydrolysis process is stored within the Myosin Head and causes a conformational change. The head bends or becomes "cocked" at an angle of approximately 90° relative to the Actin filament. This state is called the High-Energy Conformation because the energy obtained from hydrolysis is stored as potential energy in this state, much like compressing a spring. At this stage, ADP and Pi remain bound to the head.
  3. Weak Binding of the Myosin Head to Actin: In the "cocked" or High-Energy state, the Myosin Head extends towards a new binding site on the Actin filament and forms a weak, transient bond with it. This bond does not become strong until the release of Phosphate (Pi) in the next step. In a relaxed muscle, the Actin binding sites are covered by the Tropomyosin protein, which prevents Myosin from binding to Actin at this step. When a nervous stimulus for muscle contraction arrives, Calcium Ions (Ca2+) are released and bind to the Troponin protein, which moves Tropomyosin away, exposing the Actin binding sites and allowing Myosin to bind.
  4. Pi Release and Strong Binding Formation: After binding to Actin, the bound Inorganic Phosphate (Pi) molecule is released from the Myosin Head. The release of Phosphate causes another significant conformational change in the Myosin Head, which greatly strengthens its bond with Actin. This strong binding formation initiates the Power Stroke. Phosphate release acts as a trigger that forces the Myosin Head to transition from its High-Energy "cocked" state to the Low-Energy Conformation or its original state.
  5. ADP Release and Power Stroke Completion: Immediately after Phosphate release, the ADP molecule is also released from the Myosin Head. With the release of ADP, the conformational change in the Myosin Head is completed, and the head returns to its original position. During this conformational change, the Myosin Head pulls the Actin filament towards the center of the Myosin filament by a distance of approximately 10-15 nanometers. This displacement of the Actin filament is the main Power Stroke. It applies the mechanical force required for muscle contraction. After the Power Stroke is completed, the Myosin Head remains tightly bound to Actin, a state known as the Rigor State.
  6. ATP Binding (Return to Step 1): After the Power Stroke is completed and ADP is released, the Myosin Head remains in a very strong bond with Actin. If sufficient ATP is available within the cell, a new ATP molecule quickly binds to the ATP-binding site of the Myosin Head. This ATP binding reduces the affinity of the Myosin Head for Actin and causes it to dissociate from the Actin filament again, just like in the first step. Once dissociated, the Myosin Head is ready to hydrolyze new ATP and return to the "cocked" state, starting another Cross-Bridge Cycle (Step 2). Thus, as long as ATP and the necessary signal (calcium) are present, this cycle continues rapidly, causing the Actin filaments to slide over the Myosin filaments and muscle contraction to persist.

This continuous cyclical process causes the muscle fibers to shorten and muscle contraction to occur. The small displacements of each Myosin Head combine to enable the overall and powerful contraction of the muscle.

Role of Unconventional Myosins in Other Cellular Functions

In addition to muscle contraction, Unconventional Myosin proteins play many other important and diverse roles within the cell. Their functions are essential for cell structure, motility, and the transport of various components:

  • Cell Division: In eukaryotic cells, during Cytokinesis, the final stage of cell division where the cell membrane constricts to divide the cell into two daughter cells, Type II Myosin combines with Actin filaments to form a Contractile Ring.
  • Organelle and Cellular Component Transport: Type V Myosin plays a major role in the intracellular transport of Organelles (such as mitochondria, vesicles originating from the Golgi apparatus) and other large molecules (mRNA). They use the 'road' of Actin filaments to deliver these 'cargoes' to their specific destinations. Their ability to 'walk' long distances along Actin filaments (Processivity) makes this transport highly efficient. Other Myosins are also involved in Vesicle transport.
  • Cell Shape, Polarity, and Motility: Various Unconventional Myosins, such as Type I, VII, X, etc., play important roles in controlling the structure and reorganization of the Actin cytoskeleton. They enable changes in cell shape, formation of cell membrane projections or Protrusions (such as lamellipodia or filopodia formation), and overall cell movement (such as immune cells migrating towards pathogens). Additionally, they help establish and maintain Cell Polarization, meaning the functional differences in various parts of the cell.
  • Endocytosis and Exocytosis: Certain Unconventional Myosins are involved in the process of forming Vesicles from the cell membrane (Endocytosis) and the process of Vesicles fusing with the cell membrane to release their contents outside (Exocytosis). Specifically, Type I and Type VI Myosins play important roles in these processes.
  • Sensory Organ Function: The role of certain specialized Unconventional Myosins is essential for sensory functions such as hearing, vision, and balance. Myosin VIIA (MYO7A) present in the Hair Cells of the inner ear is important for the cell's sensitivity to sound waves and signal transmission. The presence of Myosin in the photoreceptor cells of the retina is also involved in signal processing.

It is clear from these various functions that Myosin protein is part of a vast and essential network of motility in living cells, which is not limited solely to muscle contraction.

Clinical Significance and Diseases Related to Myosin

Any kind of defect in the structure and function of Myosin protein can cause various serious Diseases in the human body. Some notable Diseases and syndromes caused by genetic Mutations or defects in Myosin-encoding genes are listed below:

  • Myopathies: Mutations in various Myosin genes, including Myosin II, can cause congenital myopathies, nemaline myopathy, and other types of muscle weakness, reduced function, or abnormal structure.
  • Cardiomyopathies: As the main contractile protein of heart muscle, Mutations in genes like β-Myosin Heavy Chain (MYH7) are one of the primary causes of serious heart diseases such as Hypertrophic Cardiomyopathy, where there is abnormal thickening of the heart muscle, and Dilated Cardiomyopathy, where the heart chambers become enlarged.
  • Hearing Loss and Deafness: Mutations in Myosin VIIA (MYO7A) and other Myosins present in the Hair Cells of the inner ear can cause congenital and progressive Deafness. It is also associated with syndromes like Usher Syndrome, where Deafness is accompanied by vision problems.
  • Kidney Diseases: Certain specific Myosins are also found in kidney cells, and defects in their function can cause Kidney Diseases like Nephrotic Syndrome.
  • Other Syndromes: Mutations in various Unconventional Myosin genes are associated with rare and complex syndromes like Alport Syndrome (kidney disease, hearing loss and deafness, and eye problems) and Griscelli Syndrome (albinism and immune deficiency).

Thus, it is evident how important the proper function of Myosin protein is for maintaining the health of living cells and the entire organism. Understanding the molecular basis of Myosin-related Diseases is extremely necessary for diagnosis, early detection, and the development of effective treatment methods (such as targeted therapy or gene therapy).

Conclusion

Overall, Myosin protein is an extraordinary and essential component of motility and mechanical function in eukaryotic organisms. From the powerful activity of muscle contraction to the precise transport of tiny organelles within the cell, cell division, and regulation of cell shape—the contribution of Myosin is undeniable everywhere. Its specific movement along Actin filaments, powered by ATP, forms the basis of countless processes in eukaryotic cells. The Cross-Bridge Cycle of Type II Myosin step-by-step explains the molecular mechanism of muscle contraction, showing how chemical energy is converted into mechanical work. Unconventional Myosins play important roles in transporting various cargoes within the cell and regulating cytoskeleton dynamics. Our increasing knowledge about the structure, various types, and cellular functions of Myosin protein is opening new horizons in biology and medical science. Future research is expected to unveil more profound mysteries about Myosin-related Diseases, more advanced treatment methods, and the control of cellular movement.