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endocytosis
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LDL



  1. Need for all membranes

  2. Steps same as general pathway

  3. In lysosome hydrolytic enzymes free cholesterol


    •  diffuse out of cell


  4. LDL receptor has multiple domains


    • Binding region, glycosilated parts, plasma membrane part, tail - in cytoplasm





LDL mutations



  1. Mutations can occur in ER, trans from ER to G (quality control),  binding region, clustering


    • Familial hypercholesterolemia - failure of LDL clearance

    • Treatment - low fat diet, Lipitor or Crestor (cholesterold lowering drugs)


    • LDL - FxNPXY - first tyrosine based internalization signal discovered leading to hypercholesterolemia





General pathway for receptor mediated endocytosis



  1. Ligand attach to receptor

  2. Triggers vesicle formation - buds into cell

  3. Clathrin coat falls off

  4. Fuses with endosome - ligand parts from receptor (due to pH change)

  5. Receptor is recycled back to membrane

  6. Endosome becomes lysosome


 

  • pH changes trigger outcomes - LDL dissociate from receptor as pH decreases in lysosome




Transferrin - iron carrier


  • Need for RBCs
  1. 2 iron bound to 1 transferrin bind to receptor
  2. Buds into cell
  3. Clathrin coat falls off
  4. Fuses with endosome
  5. Iron released as separate vesicle
  6. Receptor with transferrin buds out and transferrin unbinds



Growth factors - EGF (also PDGF, NGF)


  1. EGF bind to EGFR
  2. Buds into cell
  3. Clathrin coat falls off
  4. Fuses with endosome, stays separate vesicle
  5. EGF & EGFR dissolved  in lysosome
 
  • Down regulation - hormones not needed constantly like iron and LDL
  • Importance? Do they signal nucleus?



influenza


Influenza
  1. Exploitpathway
  2. Proteins on virus attach to receptor
  3. Triggers it to be engulfed
  4. Clathrin coat falls off?
  5. Fuses with endosome
  6. Viral and endosymal membrane fuse
    1. low pH triggers hydrophobic groups to be exposed and fuse with membrane
  7. Ejection of viral nucleocapsid
  8. Rabies too, specific to Ach receptor - neuromuscular junctions



toxins



Diptheria - type - what does that mean Shiga - type - what is the type What diptheria does What shiga does Released from endosome Stay in endosome - absorbed by golgi, ER. Released into cytoplasm after modifications?    


transcytosis


  • Transport of proteins from one domain to another
  • - same as endocytosis:
  • IgA - receptor bind to IgA dimer basolateral
    • Endocytized and receptor-IgA ejected lumen/apical
  • IgG - Fc receptor bind to IgG - apical pH 6 (higher affinity)
    • Endocytized and release basolateral (pH 7)
    • Receptor recycled



phagocytosis


  • Macrophages Digest aging RBCs in spleen
  • Neutrophil digest bacteria
    • G protein bacteria protein receptor influences cell topography - move toward bacteria (actin pseudopod)
  • Same process as endocytosis - engulf and make phagosome - granules fuse with lysosomal enzymes



bacterial adaptations to escape lysosomal killing


Bacterial adaptations to escape lysosomal killing
  1. Inhibit fusion of granules clamydia, toxoplasma
  2. Waxy coat makes it enzyme resistant leprosy
  3. Neutralize enzymes salmonella, leishmania
  4. Escape endosome listeria, trpanosoma