Question

Give examples of human pathologies related to dysregulation of actin cytoskeleton, microtubule, or associated motors (myosins, kinesins, dyneins)

Answer 1

Cytoskeleton

The cytoskeleton is responsible for cell shape, motility (movement) of the cell as a whole, and motility of organelles within a cell. There are three types of filaments in the cytoplasm of most vertebrate cells: microfilaments, microtubules, and intermediate filaments. All of these filament systems share a critical feature: They are composed of proteins that have the unique property of being able to self-assemble into a filamentous network. Imagine a pile of bricks that could assemble by themselves into a wall; the proteins that make up the fibers of the cytoskeleton are able to do just this. The proteins that make each of the three different filament systems assemble into only the structure characteristic of that filament.

Unlike the human skeleton, the cytoskeleton is extremely dynamic, meaning the filament systems are able to lengthen or shorten very rapidly. This dynamic nature of the cytoskeleton is necessary for cells to be able to change shape, complete cell division, or migrate, and represents one of the cytoskeleton's most important features. Each of the self-assembling proteins has a characteristic concentration, called the "critical concentration," below which the monomer state is favored and above which the polymer state is favored. Increasingly, the subunit concentration favors filament building, and decreasing it favors filament deconstruction. This property allows the cell to rapidly control cytoskeleton structure.

Microfilaments

The microfilament system is a network of filaments 6 nanometers (nm) in diameter that are important for anchoring plasma membrane proteins, for producing cell movement, and for cell division. The base filament is composed of a protein called actin that is 42 kilodaltons (kd) in weight. Actin is also the protein that forms the thin filaments found in muscle. When purified actin is incubated in a test tube, 6 nm filamentous structures are formed. These threads consist of side-by-side actin monomers that twist around each other in a helix. Inside cells, actin exists in two states, the monomeric protein, called G-actin (for globular actin) and the 6 nm filament, called F-actin (for filamentous actin). The factor that determines the relative proportions of F-actin and G-actin is the concentration of actin protein. Each microfilament has a fast-growing, or "plus," end, and a slow-growing, or "minus," end. In most cells the plus ends of the filaments are oriented toward the edge of the cell. In this way rapid polymerization of actin monomers onto the plus ends of microfilaments can produce protrusions on the cell surface called pseudopods . These extensions are critical for the ability of cells to migrate in a directional fashion.

Microfilaments exist in their highest concentration in association with the cell periphery, where they are believed to play an important role in anchoring membrane proteins. Microfilaments can also be organized into bundles, called stress fibers, which serve as contractile elements, somewhat like little muscles, within cells. These structures are important for maintaining connections between the cell and the surface on which it grows. In addition, these structures may be important for producing contractility to generate directional force during cell motility. A third microfilament-based structure, the contractile ring, is critical for the separation of a cell into its two progeny during cytokinesis.

In most cells the concentration of actin exceeds the critical concentration for microfilament assembly, yet the actin is not entirely assembled into filaments. This occurs because cells make a variety of "actin-associated" or "actin-binding" proteins. One example of an actin binding protein is the G-actin-binding protein profilin. When bound to profilin, actin monomers cannot assemble into filaments. Binding of actin by profilin can effectively reduce the concentration of free actin monomer to below the critical concentration. The actin-binding activity of profilin is regulated in cells. Certain stimuli will cause profilin molecules to release their bound actin monomers, effectively increasing the concentration of actin and thereby stimulating actin assembly. Thus cells can control the relative proportions of G-actin and F-actin.

actin molecul minus ond 37 m plus o nd

Helical structure of actin molecules.

In general, the functions of actin-associated proteins are to modify the properties of the microfilament network in cells. Some filament-associated proteins, for example the protein tropomyosin, bind along the length of the filament to stiffen it. There are also proteins such as villin or filamin that bind microfilaments together side by side to produce bundles of actin filaments. Other actin-binding proteins cross-link actin filaments to form meshlike structures such as those found in association with the cell membrane. Cells can also control the length of filaments through the action of proteins that can cut filaments to produce two shorter filaments. To keep the filaments a certain length, cells produce "capping" proteins that bind to the ends and prevent the addition of new actin subunits. By modulating the state of the microfilament network the cell can control the physical properties of the cytoplasm such as rigidity and viscosity.

One of the most interesting types of actin-associated proteins is a family of enzymes , called myosins, which have the ability to convert chemical energy into movement. The characteristic property of these so-called myosin molecular motors is their ability to bind actin in an adenosine triphosphate

Answer 2

Motor proteins utilizing the cytoskeleton for movement fall into two categories based on their substrates: Actin motors such as myosin move along microfilaments through interaction with actin. Microtubule motors such as dynein and kinesin move along microtubules through interaction with tubulin. There are two basic types of microtubule motors: plus-end motors and minus-end motors, depending on the direction in which they "walk" along the microtubule cables within the cell.

Myosins are actin motors and form myosin complexes consisting of two heavy chains with motor heads and two light chains. Derived from the Greek word for muscle, myosin is the protein responsible for generating muscle contraction. By non-processively walking along actin filaments, many molecules of myosin generate enough force to contract muscle tissue. Myosins are also vital in the process of cell division. They are also involved in cytoplasmic streaming, wherein movement along microfilament networks in the cell allows organelles and cytoplasm to stream in a particular direction. Eighteen different classes of myosins are known.

Kinesins are a group of related motor proteins that use a microtubule track along which to "walk." They are vital to the movement of chromosomes during mitosis and are also responsible for shuttling mitochondria, Golgi bodies, and vesicles within eukaryotic cells. Kinesins typically contain two heavy chains with motor heads which move along microtubules via a pseudo-processive asymmetric walking motion, that can be towards the plus-end or the minus-end, depending on the type of kinesin. Fourteen distinct kinesin families are known, with some additional kinesin-like proteins that cannot be classified into these families.

Dyneins are microtubule motors capable of a sliding movement. Dynein complexes are much larger and more complex than kinesin and myosin motors. Axonemal dynein facilitates the movement of cilia and flagella, and cytoplasmic dynein facilitates transport of intracellular cargos. Compared to 15 types of axonemal dynein, only two cytoplasmic forms are known.