Eukaryotic Cells Cytoskeleton part 1

• Eukaryotic cells' cytoskeletal system comprises three main kinds of filaments: microfilaments, microtubules, and intermediate filaments

Learning Outcomes

• To understand composition of cytoskeletal system in animal cells
• To describe main cellular processes depending on cytoskeleton
• Understand role of cytoskeleton in disease

Cell Cytoskeleton

• Dynamic three-dimensional structure filling cytosol
• A filamentous network
• Maintains cell shape
• Regulates and implements dynamic cellular functions

Functions

• Dictates cell shape and orientation
• Facilitates organelle movement
• Important for cell division, and migration

Cytoskeletal System Structure

• Each filament type forms by polymerization of a distinct protein subunit
• Each has its own characteristic shape and intracellular distribution
• Each has a distinct size, referring to the diameter

Microfilaments

• Polymers of the protein actin
• Thinnest filament
• Fine, thread-like protein fibres, with a diameter of ~7nm
• Composed of actin subunits
• Can exist as a free monomer called G-actin (globular)
• Can exist as part of a linear polymer microfilament called F-actin (filamentous)
• Consist of protein polymers
• Contain thousands of identical subunits
• Allows for rapid reorganization

Actin Filaments

• Are ubiquitously expressed
• Give shape to the cell surface
• Important for motility, refers to the ability to move spontaneously and actively, consuming energy
• Essential for mobility, refers to the ability of an object to be moved
• Cause contraction of cells during cell division

Microfilament Functions

• Dictate Cell shape and orientation
• Cause muscle contraction
• Facilitate movement of organelles
• Important for cell division
• Facilitate Cell migration

Actin Binding Proteins (ABPs)

• Actin function depends upon interaction with ABPs
• There are Over 150 known ABPs
• ABPs comprise 25% of cellular protein
• Bind to g-actin and regulate polymerisation
• Bind to f-actin and impart structural diversity

Actin Binding Proteins that Modify Actin Function

• Binds to G-actin and regulate polymerisation
• Latrunculin, a natural product/toxin from sponges, sequesters G-actin and prevents F-actin assembly
• Gelsolin, cytoplasmic and calcium-regulated, is a key ABP regulating actin filament assembly and disassembly
• ABP binds to f-actin and imparts structural diversity

Actin and Cell Migration

• ABPs remodel cellular cytoskeleton
• Important for cell migration
• Cellular migration requires orchestrated movement of cells in particular directions to specific locations
• Tissue formation during embryonic development, embryogenesis
• Wound healing, axon growth, and Immune responses such as phagocytosis

Phagocytic Cell Migration

• Phagocytic cells are attracted to damaged tissue by chemical signals known as chemokines
• Neutrophils are then followed by monocytes, which are followed by macrophages
• Cellular migration occurs in 3 stages: protrusion of leading edge, attachment of leading edge which provides traction, and contraction which refers to movement of main cell body forward
• Rapid actin polymerisation occurs at the the cell's front edge
• Actin filaments link the cell to extracellular substrates

Actin and Cell Movement

• Contraction in cell movement refers to movement of main cell body forward
• Myosin is involved
• The myosin head region interacts with actin
• The myosin tail region binds to plasma membrane
• Movement of myosin along actin filament causes membrane and cell contraction

Actin Filament Dysfunction

• First case of neutrophil actin dysfunction (NAD) reported in 1974, involving a male infant with severe neutrophil motility disorder and poorly polymerizable actin
• It is a genetic disorder
• Neutrophil motility, refers to the ability to move spontaneously and actively, consuming energy
• Neutrophils migrate to the site of infection, ingest and destroy pathogens, after releasing granule contents and active oxygen
• These activities are closely associated with a rapid reorganization of the cytoskeleton via actin polymerization, cross-linking, anchoring to membrane, and depolymerization, controlled by various actin-binding proteins
• Neutrophil actin dysfunction is associated with impaired phagocytic uptake

Actin-Targeting Drugs

• Stabilize, depolymerize, polymerize, or rearrange F-actin filaments
• Responsible for changes of cellular function
• Divided into three major classes: Cytochalasins, Latrunculins, and Jasplakinolides