Cytoskeleton and Cell Movement

• The cytoskeleton provides the basis for cell movement and intracellular transport
• Actin cytoskeleton also has a role in skeletal muscle function

Key Components of the Cytoskeleton

• Microfilaments (Actin filaments) are primary drivers of movement
• Intermediate filaments
• Microtubles
• They make up around 3-6% of the cell, specifically beneath the plasma membrane

Microfilaments

• Possess nucleotide-binding sites which bind to ATP and ADP
• They polymerize into actin
• They have polarity with barbed (+) and pointed (-) ends
• Specific mechanisms include cell crawling, immune cell migration, and wound healing

Cellular Movement

• Actin filaments polymerize in the direction of intended movement
• Lamellipodia (cell protrusions) form and attach to a substrate
• Myosin II then contracts, pulling along newly formed actin filaments

Polymerization Regulators

• Profilin aids polymerization
• Capping proteins prevent further growth
• Severing proteins, like gelsolin and ADF/cofilin will break existing filaments

Functional Dynamics

• The functional dynamics of the cytoskeleton include cross-linking or bundling into complex structures
• They are critical for maintaining cell shape, muscle contraction, and cell crawling mechanisms

Intracellular Transport

• Microtubule-based transport is the primary mechanism
• Motor proteins enable muscle cell contraction and cellular migration
• Dynein moves towards the negative pole (retrograde)
• Kinesin moves towards the positive pole (anterograde)
• The process is ATP-dependent for the transport of vesicles and organelles

Specialized Microtubule Structures

• Cilia are projections that move from the cell membrane
• Respiratory cilia move mucus
• Flagella only exist in sperm cells
• Centrioles do cell division

Intermediate Filaments

• There is structural diversity among them
• They can be divided into 6 classes
• They are roughly 10nm wide
• Main component of hair

Intermediate Filament Classes

• Over 70 distinct intermediate filament proteins exist
• Keratins (Acidic and Basic) are in Epithelia
• Some are called "keratins"
• Desmin exist in muscle
• GFAP exists in glial cells
• Neurofilaments exist in neurons
• Lamins exist in the nuclear envelope
• Nestin exists in neural stem cells

Intermediate Filament Characteristics

• Semi-permanent tissue structures
• Phosphorylation controls disassembly
• They are involved in cell-cell adhesion
• Provide mechanical strength throughout the cell

Microtubules

• Intracellular transport
• Microtubule Associated Proteins (MAP) attach to the microtubule and stop them from deep memorizing

Instability

• The MAPS stabilize their dynamic so it will have higher memory
• MAPs stabilize microtubules through protein interaction e.g. (TAU)

Regulating Function

• Function tightly regulated by phosphorylation
• Alzheimer's disease will cause them to not associate adding a phosphate group to proteins

GTP Hydrolysis

• Gtp is hydrolyzed during polymerization immediately following polymerization
• Intracellular transport

Microtubule Dimensions

• There are roughly around 25nm
• Microtubule Associated Protein (MAP)
  • Stabilize microtubules with protein interaction e.g., tau
  • Alzheimer's disease

Tubulin Dimers

• Microtubules are composed of Tubulin Dimers that are subunits of the protein "tubulin"
• They consist of α-tubulin and β-tubulin
• They have a polar structure
• 13 polymers form the circumference
• Alpha-tubulin is at the (-) end
• Beta-tubulin is always added at the (+) end
• All microtubules are attached to a centrioles in the centrosome
• The centrosome us made up of microtubules

Actin and Muscle Function

• Actin cytoskeleton is also the basis of skeletal muscle function

Structural Muscle Levels

• Muscle fiber
• Myofibril
• Sarcomere (functional unit)
  • Contains primary contractile elements
  • There are Key Molecular components:
    • Thin filaments (Actin)
• Actins Regulatory Proteins controls muscle contraction: -Tropomyosin -Troponin complex -Calcium sensitive protein triggers muscle contraction, and consists of 3 subunits

Contractile Proteins

Key Molecular components:

• Primary contractile protein, runs entire length of sarcomere, contains regulatory proteins
• Thick filaments (Myosin)
  • Motor protein, generates mechanical force, interacts with actin .

Mechanism During Resting State

• Tropomyosin blocks myosin-binding sites
• Calcium channels closed
• Actin filaments held in the inhibited configuration

Calcium Release

• Binds to troponin C, causes conformational protein changes - ATP-powered moves -Sarcomere shortens
• Precise/ coordinated Molecular movement.

Muscle Contraction Requires

• Sliding theory
• Myosin head pulls actin Muscle contraction

Mutations

• Mutations or the poisoning of the cytoskeleton can result in specific diseases. Also a significant drug target (i.e. vincristine, taxol)

Microfilament (Actin) Related Diseases

• Disrupted positive and negative cellular movements
• Negative movements include:
  • Cancer metastasis, abnormal cell migration, uncontrolled spread Angiogenesis in diabetic Retinopathy which leads to Blood cells proliferation & disperse into the Retina & displace retina -Neuropathic pain related Multiple sclerosis

MICROTUBULES disorders

Neurodegeneration

Six Major Disrupted II Classes

1 Kevatins epithelial 2 Desmin muscle 3 GFAP glial cells 4 Neurofilaments nervous 5 Launius nuclear envelope Type 1 11 disorders Hmin

Neurodegeneration disorders

-parkninsons’s, Alzheimer's

. Frontotemporal dementia and other tauopathies

Disrupted Systems

• Respiration
• Reproductive

Microtubule pathologies examples

Neurodegeneration:

Drug Action

Vinicistine& Taxol effect drug:

-Vinicistine
action: destabilizesmicotables prevents: Microtubulepolymerisation Disrupts Mitoticspindle

Molecular action:

  -Binds to - tublin protein  prevents

MICROTUBULEDESTABILIZERS action:

• Stops cell division
• Triggers apoptosis in rapidly dividing
• Binds to: Microtubule
  Stabilizesexistingstructures
• Preventsmicrotubuledisassembly Locksmicrotubulesinfixedconfiguation disrupts normal cellular division. Interrupts:
• rapidlydyning
• PreciseMolculartargeting
• Interruptcellular

The cytoskeleton, including microfilaments (actin), intermediate filaments and microtubules, drives cell movement and intracellular transport. Actin filaments polymerize in the direction of movement, forming protrusions like lamellipodia that attach to a substrate. Myosin II-mediated contraction then facilitates cellular movement.