Cytoskeleton 2

Cellular Biology & Homeostasis

Overview

  • Focus on the cytoskeleton and its role in maintaining cellular structure and function.

Learning Objectives

  1. Structure and Function

    • Microtubules

      • Dynamic instability, MT-organizing center, MT-associated proteins, cilia, and flagella.

    • Intermediate Filaments

      • Cell junctions, mechanical stability, mutations affecting this filament.

  2. Drug Interactions

    • Understand how various drugs can modify the functioning of microtubules.

      • Examples provided.

Microtubules

Basic Structure

  • Composed of polymers of the protein tubulin.

  • Tubulin heterodimer consists of:

    • Alpha-tubulin

    • Beta-tubulin

  • Each tubulin has a binding site for GTP:

    • Bound to alpha-tubulin is trapped (not hydrolyzed nor exchanged).

    • GTP in beta-tubulin hydrolyzes to GDP during polymerization.

    • GDP exchanges for GTP on depolymerization.

Composition

  • Microtubules consist of:

    • Alpha-beta tubulin heterodimers

    • Arranged head to tail

    • Forming hollow cylindrical structures

    • Built from protofilaments.

Dynamic Instability

  • Growth and Shrinkage

    • Process called dynamic instability

      • Allows for alternating growth (assembly) and shrinkage (disassembly) phases.

    • Structural plasticity relies on the activities of GTP-binding domain of beta-tubulin.

  • Mechanism

    • Addition of GTP-containing tubulin promotes growth.

    • Rapid hydrolysis of GTP leads to depolymerization.

Clinical Relevance of Microtubule Dynamics

Applications

  • Cancer Therapy

    • Drugs can stabilize/destabilize microtubule dynamics to disrupt mitosis, inducing cell death.

  • Neurodegenerative Diseases

    • Dysfunctional microtubule-associated proteins contribute to diseases like Alzheimer's.

  • Cell Migration and Metastasis

    • Microtubule dynamics facilitate cell motility, key in wound healing and cancer metastasis.

  • Developmental Biology

    • Critical for cell division and differentiation.

  • Pathogen Response

    • Some pathogens utilize microtubules for cellular entry/movement.

Microtubule Organizing Center (MTOC)

Structure

  • Microtubules originate from the MTOC, primarily the centrosome in animal cells.

  • Centrosome

    • Composed of two cylindrical centrioles involved in spindle fiber development during cell division.

Function during Mitosis

  • Rearrangement forms a bipolar mitotic spindle for chromosome alignment and segregation.

Microtubule-Associated Proteins (MAPs)

Role in Transport

  • Transport vesicles along microtubules using MAPs:

    • Kinesin: Moves towards the (+) end.

    • Dynein: Moves towards the (-) end.

Types of Kinesin

  • ATP hydrolysis in globular heads generates movement along microtubules.

  • Kinesin transports intracellular cargo toward the (+) end; dynein transports toward the (-) end.

Cell Polarity

  • MAPs can polarize a cell, enabling targeted transport of organelles and vesicles.

Cilia and Flagella

Structure and Function

  • Microtubules provide structural support for cilia and flagella.

  • Movement Mechanism

    • Dynein motor proteins facilitate bending and force generation for movement.

Functionality

  • Cilia: Moves fluids (e.g., mucus in respiratory epithelium).

  • Flagella: Propels cells in aqueous environments (e.g., sperm).

Drugs Affecting Microtubules and Actin Filaments

Microtubule-Specific Drugs

  • Taxol: Stabilizes microtubules, preventing depolymerization.

  • Colchicine: Prevents polymerization.

  • Vinca Alkaloids: Interfere with mitotic spindle formation.

Intermediate Filaments

Structure and Functions

  • No polarity; not involved in cell movement; no associated motor proteins.

  • Line nuclear envelope, forming a protective cage around DNA and providing mechanical stability.

Types and Distribution

  • Major examples: keratin, nuclear lamins, vimentin.

  • Important for maintaining mechanical stability and structure in various tissues.

Clinical Relevance

  • Dysfunctional keratin networks can lead to diseases like epidermolysis bullosa simplex.

Conclusion on Cytoskeleton

  • Microtubules: Critical for cell shape, chromosome movement, and transport.

  • Intermediate Filaments: Provide mechanical strength and stability throughout the cell.