Actin Filaments and Cell Movement

• The cytoskeleton is essential for cell movement and intracellular transport, and the actin cytoskeleton plays a crucial role in skeletal muscle function.

Key components of the Cytoskeleton

• Microfilaments (actin filaments)
• Intermediate filaments
• Microtubules

Microfilaments (Actin Filaments)

• Made of actin monomers.
• Located beneath the plasma membrane.
• They are 3-6nm .
• Primarily drives cell movement
• Requires nucleotide binding (ATP or ADP)
• Polymerizes into filaments with positive (barbed) and negative (pointed) ends

Specific Mechanisms

• Cell crawling
• Immune cell migration
• Wound healing

Cellular Movement

• Involves actin filaments polymerizing in the direction of movement.
• Lamellipodia (cell protrusions) form and attach to the substrate, followed by myosin II contraction, which pulls the cell along newly formed actin filaments.

Polymerization Regulators

• Profilin enhances polymerization.
• Capping proteins prevent further growth.
• Severing proteins (e.g., gelsolin, ADF/cofilin) break existing filaments.

Functional Dynamics

• The cytoskeleton cross-links or bundles into structures and is crucial for maintaining cell shape, muscle contraction, and cell crawling mechanisms.

Intracellular Transport

• Accomplished primarily through microtubule-based transport.
• Motor proteins such as dynein (retrograde transport towards the negative pole) and kinesin (anterograde transport towards the positive pole) enable muscle cell contraction and cellular migration.
• This is an ATP-dependent process for vesicles and organelles.
• Specialized microtubule structures include cilia (projections that enable movement) and flagella (e.g., in sperm).

Intermediate Filaments

• Offer structural diversity
• They are 10nm
• Are divided into six classes.

Intermediate Filament Classes

• Keratins (acidic and basic) found in epithelial cells.
• Desmin in muscle tissue, especially skeletal muscle.
• GFAP (glial fibrillary acidic protein) in glial cells.
• Neurofilaments in neurons.
• Lamins in the nuclear envelope.
• Nestin in neural stem cells.

Characteristics of Intermediate FIlaments

• Semi-permanent tissue structures
• Stabilize the structure of the nuclear membrane
• Involved in cell-cell adhesion
• Provide mechanical strength.
• Controlled via phosphorylation

Microtubules Structural Composition

• Consists of tubulin dimers (α-tubulin and β-tubulin).
• Polar structure with 13 polymers forming the circumference.
• Alpha-tubulin is at the negative (-) end.
• Beta-tubulin is at the positive (+) end.
• All microtubules attach to a structure within the centrosome

Centrosome

• Specialized organelle composed of microtubules

Dynamic Instability

• GTP is hydrolyzed
• Constant assembly/disassembly mechanism
• This allows for rapid changes in structural support

Microtubule-Associated Proteins (MAPs)

• Attach to microtubules and prevent them from disassembling.
• Stabilize their dynamic instability through protein interactions (e.g., TAU).
• Function tightly, with regulation by phosphorylation.

Alzheimer's Disease

• Associated dynamic instability from the addition of a phosphate group.

Muscle Tissue Structure

• Structural levels: muscle fiber, myofibril, and sarcomere (the functional unit containing contractile elements).

Sarcomere Components

• Thin Filaments (Actin)
• Thick Filaments (Myosin)
• Regulatory Proteins

Thin Filaments (Actin)

• Primarily contractile protein
• extends along the sarcomere
• Contains regulatory proteins

Thick Filaments (Myosin)

• Motor protein that generates mechanical force through interaction with actin

Regulatory Proteins

• Tropomyosin wraps around actin filaments, blocking myosin-binding sites.
• Troponin complex: Calcium-sensitive protein triggering contraction, consisting of troponin C (calcium binding), troponin I (inhibitory), and troponin T (tropomyosin binding) subunits.

Muscle Contraction Mechanism

• Resting State: Tropomyosin blocks binding sites
• Calcium activation: Channels floods muscle cells, calcium binds to troponin C, exposing myosin binding sites.
• Cross-Bridge Cycling: ATP hydrolysis powers myosin heads to move along actin, shortening the sarcomere through coordinated molecular movement.
• Energy Requirements: Sliding filament theory enables force generation and muscle contraction through a precise, coordinated movement.

Microfilament (Actin) Related Diseases

• Impact muscle contraction mechanisms.
• Disrupt immune cell migration, compromising the immune response.

Wound Healing

• Wound repair is also comprimised
• Repair protein generation is impacted
• Time regeneration is comprimised

Cancer Metastasis

• Abnormal cell migration
• Uncontrolled cellular spread

Angiogenesis in Diabetic Retinopathy

• Epithelial cell migration
• Multiple sclerosis
• Neuronal Sprouting: Resulting in neuropathic pain and spinal cord issues.

Microtubule Disorders

• Neurodegeneration
• Parkinson's disease, Alzheimer's disease, frontotemporal dementia, related tauopathies

TAU

• A stabilizing protein for microtubules.

Ciliopathies

• Affects the respiratory & reproductive systems
• Involves impaired cilia/flagella function
• Compromises sensory system
• Causes developmental abnormalities.

Muscular Dystrophy

• Duchenne muscular dystrophy results from a mutation in MAP.

Intermediate Filament Related Disorder

Type I & II Disorders (Keratins & Desmin)

• Epidermolysis Bullosa Simplex
• Skin fragility
• Cellular structural weakness

Type III Disorders (GFAP)

• Amyotrophic Lateral Sclerosis (ALS)
• Neurological degeneration
• Motor neuron dysfunction

Type IV Disorders (Neurofilaments

• Parkinson's disease
• Alzheimer's disease

Type V Disorders (Lamins)

• Divine systemic condition
• Lipodystrophy
• Muscle laminopathies
• Neurological disorders
• Systemic laminopathies

Type VI Disorders (Nestin)

• Related category
• Affects neural stem cells

Vincristine and Taxol

• Used as drug targets

Vincristine Mechanism

• Destabilizes microtubules, preventing polymerization and disrupting mitotic spindle formation, leading to cell cycle arrest and apoptosis in rapidly dividing cells.

Taxol (Taxanes)

• Stabilizes existing microtubule structures
• Prevents disassembly, locking microtubules in a fixed configuration
• Interrupts normal cellular division.

Clinical Applications of Vincristine and Taxol

• Used in lymphoma, leukemia, hodgkin's lymphoma, ovarian cancer and breast cancer

Shared Characteristics of Vincristine and Taxol

• Target rapidly dividing cells
• Primarily used in cancer treatment
• Interrupt cellular division processes
• Precise molecular targeting occurs in both.

Explore the role of actin filaments in cell movement and skeletal muscle function. Learn about microfilaments, their structure, and how they drive cellular movement through polymerization and interaction with myosin II. Discover the regulators of actin polymerization.