Microtubules

Overview

• Introduction 
  • cellular structural protein with a hollow tubular structure
• Structure
  • composed of polymerized dimers of α- and β-tubulin
    • each dimer has 2 GTP molecules bound
  • constant assembly (slow) and disassembly (fast)
    • clinical importance
      • Chédiak–Higashi syndrome (CHS)
        • etiology
          • a disease caused by a microtubule polymerization defect
        • resulting in decreased chemotaxis, degranulation, phagocytosis
        • AR inheritance
        • presentation
          • recurrent pyogenic infections
            • particularly S. aureus
          • partial albinism
          • peripheral neuropathy
• Function
  • component of many important cellular structures
    • cilia
      • 9+2 arrangement of microtubules
      • axonemal dynein
        • ATPase that attaches the peripheral 9 doublets
        • causes bending of cilium by binding differentially to doublets
      • also forms the core of flagella
      • clinical importance
        • Kartagener syndrome   
          • immotile cilia disease
          • cause
            • dynein arm defect  
          • presentation
            • male and female infertility
              • sperm are immotile (no functional flagellar tail)
              • Fallopian tubes cannot sweep egg and sperm towards each other 
            • bronchiectasis
            • recurrent sinusitis
              • mucus with bacteria and particles cannot be removed
            • associated with situs inversus
    • mitotic spindles
    • molecular motor proteins 
      • mediates intracellular transport
      • 2 types 
        • kinesin 
          • cell center → periphery
          • anterograde to microtubule
          • e.g. transports neurotransmitter vesicles down axon towards synapse
          • also transports Herpes zoster virus particles from the dorsal root ganglion during reactivation as shingles 
        • dynein 
          • periphery → cell center
          • retrograde to microtubule
          • e.g. lipid transport from synapse back to Golgi apparatus
• Pharmacologic importance
  • mebendazole
    • class: antihelminthic
    • mechanism of action
      • ↓ microtubule synthesis in worms
  • griseofulvin
    • class: antifungal
    • mechanism of action
      • deposits in new keratin and disrupts microtubule polymerization
    • uses
      • active against dermatophytes only
  • vincristine/vinblastine 
    • class: anti-cancer
    • mechanism of action
      • ↓ microtubule polymerization
        • inhibits mitosis
    • side effects
      • peripheral neuritis
      • areflexia
      • myelosuppression
  • paclitaxel (taxol)
    • class: anti-breast cancer
    • mechanism
      • ↑ stability of microtubule and does not allow disassembly
        • inhibits mitosis
  • colchicine 
    • class: anti-gout
    • mechanism of action
      • binds free tubulin
      • ↓ microtubule polymerization
• inhibits leukocyte/granulocyte migration