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Endocytosis and Lysosome Formation

Endocytosis and Lysosome Formation. The Endolytic Pathway. Lysosomes and Endosomes. Early endosome pH 6.5-6 sorting endosome Late endosome pH 5.5-5 Lysosome pH 5-4.5. Structure of Lysosomes. Protein rich membranes Lamp/Limp family of glycoproteins Unusual lipids

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Endocytosis and Lysosome Formation

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  1. Endocytosis and Lysosome Formation The Endolytic Pathway

  2. Lysosomes and Endosomes • Early endosome • pH 6.5-6 • sorting endosome • Late endosome • pH 5.5-5 • Lysosome • pH 5-4.5

  3. Structure of Lysosomes • Protein rich membranes • Lamp/Limp family of glycoproteins • Unusual lipids • lyso-bisphosphatidic acid • thought to protect lysosomal membrane lipids from action of lumenal lipases • Multivesicular bodies (late endosomes/lysosomes) • invagination of the limiting membrane • forms internal membranes • TM proteins can segregate into limiting or internal membranes • limiting membrane can be recycled, internal is not

  4. Phagocytosis

  5. Endocytic Mechanisms • cytockeletal element involvement • macropinocytosis • phagocytosis • clathrin coated pits • calveolin coated calveolae • non-coated pit pinocytosis

  6. Receptor-Mediated Endocytosis • Clathrin-coated pits • AP1, 2, 3, 4 • heterotetramer •  & γsubunits target •  subunits bind clathrin •  binds receptor signal sequence • clathrin triskelion • hexamer of 3 heavy & 3 light chains

  7. Formation of Coated Pit • AP2-receptor interaction • Receptor clustering • Clathrin recruitment • Dynamin collar assembly • Budding • Uncoating & recycling of components

  8. Coated Pit Targeting Sequences • FxNPxY • Yxx • Tyrosine residue in these contexts is necessary & sufficient to mediate AP2 interactions and subsequent clathrin assembly

  9. LDL EGFR CD4 Pumps Endocytosis Kinetics • Bulk rate • measurement of lipid movement • Binding-studies & Turnover • experiments designed to measure ligand-receptor interaction strength and rate of receptor/ligand destruction, synthesis and replacement

  10. Calveolae Or as they're better known… • Plasmalemmal vesicles • Associated with lipid rafts • Membrane lipid cycling • Raft-associated protein endocytosis/exocytosis • Inner leaflet proteins • acylated proteins • prenylated proteins • Outer leaflet proteins • GPI-linked • Some TM proteins that interact specifically with glycosphingolipids/cholesterol

  11. Calveolae • Calveolin • high-affinity cholesterol binding protein

  12. Macropinocytosis in Action

  13. Pretty Colored Vesicles • Gold dust through the endolytic pathway • coated pits (CP) • early endosome (EE) • late endosome (LE) • lysosome (LY)

  14. Recycling Membrane Components from Endosomes • Tubulovesicular morphology • membrane concentrated tubules • bud & recycled directly & indirectly

  15. Ok, It's In the Cell. Now What • pH dependent interactions • affects protein-protein interactions in endolytic compartments • Acidification mediated by H+ ATPase • vacuolar ATPase

  16. Some Examples of Receptor Mediated Endocytosis • Receptor recycling • LDL-LDLR • transferrin-transferrin receptor • Receptor destruction • EGF-EGFR

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