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• Last Class:
• 1. transportation at the plasma membrane
• A. carrier protein, B. channel protein
• 2. intracellular compartments
• A. nucleus, B. Endoplasmic Reticulum
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• Intracellular Vesicular Traffic
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The endocytic and biosynthetic-secretory pathways
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Vesicular transport
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The intracellular compartments of the eucaryotic cell in the biosynthetic-secretory and endocytic
pathways
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Utilization of different coats in vesicular traffic
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Clathrin-coated pits and vesicles
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The structure of a clathrin coat
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The assembly and disassembly of a clathrin coat
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The role of dynamin in pinching off clathrin-coated vesicles from the membrane
Shibire mutant in drosophila
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A current model of COPII-coated vesicle formation
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The postulated role of SNAREs in guiding vesicular transport
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The structure of paired snare
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A model for how SNARE proteins may concentrate in
membrane fusion
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Dissociation of SNARE pairs by NSF after a membrane fusion cycle is completed
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A postulated role of Rab protein in facilitating the docking of transport vesicles
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The entry of enveloped viruses into cells
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• Transport from the ER through the Golgi apparatus
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The recruitment of cargo molecules into ER transport vesicles
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Retention of incompletely assembled antibody molecules in the ER
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Vesicular tubular clusters
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A model for the retrieval of ER resident proteins
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The Golgi apparatus
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The functional compartmentalization of the Golgi apparatus
Notice of multiple steps involving glycosylation
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Two possible models explaining the
organization of the Golgi apparatus and the
transport of proteins from one cisterna to the next
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• Transport from the trans Golgi nextwork to Lysosomes
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LysosomesLow pH
Full of Acid hydrolases
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The structure of mannose 6-phosphate on a lysosome enzyme
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The transport of newly synthesized lysosomal hydrolases to lysosomes
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• Transport into the cell from the plasma membrane endocytosis
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Phagocytosis by a macrophagePhagocytosis: large particle, >250nm
Pinocytosis: fluid, liquid, 100 nmOne macrophage and two red blood cells
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The formation of clathrin-coated vesicles
from the plasma membrane
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Caveolae in the plasma membrane of a fibroblast
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A low-density lipoprotein (LDL)
particle
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Normal and mutant LDL receptor
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The receptor-mediated endocytosis of LDL
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Possible fates for transmembrane receptor proteins that have been endocytosed
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Storage of plasma membrane proteins in recycling endosomes
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Sorting of membrane
proteins in the endocytic pathwayGreen: EGF-EGFRRed: transferrin and its receptor
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The sequestration of endocytosed
proteins into internal
membranes of multivesicular
bodies
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• Transport from the trans Golgi network to the cell exterior: exocytosis
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The constitutive and regulated secretory pathways
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The three best-understood pathways of protein sorting in the trans Golgi network
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Exocytosis of secretory vesicles
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Electron micrographs of exocytosis in rat mast cells
Release of histamine
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Exocytosis as a localized responsesBeads attachment
localized the release
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Model of lipid rafts in the trans Golgi network
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The formation of synaptic vesicles
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Summary
•Intracellular vesicular traffic, SNARE, GAB, Clathrin, Dynamin, Adaptin
•ER->Golgi, COPII, COPI
•Golgi->lysosome, acid hydrolases, M6P
•endocytosis, phagocytosis, pinocytosis, clathrin-coated pit, caveolae,
•Exocytosis, constitutive and regulated mechanisms
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•Cell Signaling 1: General Concepts
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A simple intracellular signaling pathway
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Extracellular signaling molecules bind to receptors
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Signals can be tranmitted either short or long distances (I)
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Signals can be tranmitted either short or long distances (II)
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For Long distance, two typical ways
Endocrine signalingDifferent cells need specific ligands and receptors
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Synaptic signalingMore efficient, same set of ligands and receptors
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Signaling via GAP JunctionsNo ligand-receptor system needed
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Combinatory effect of multiple inputs
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Different receptor type and intracellular signaling molecules determine the ultimate response
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Many signaling molecules have short lifetime
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NO (nitric oxide) induces the relaxation of SMCThe function of viagra is to inhibit cyclic GMP phosphodiesterase, hence elongate the lifetime of cyclic GMP and relaxation
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2 steps of responses may occur upon stimulation
Secon
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Cell Surface receptors belong to three classes: 1. ion-channel-linked receptors, 2. G-protein-linked receptors, 3. enzyme-linked receptors
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Cell Surface receptors belong to three classes: 1. ion-channel-linked receptors, 2. G-protein-linked receptors, 3. enzyme-linked receptors
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Different Kinds of intracellular proteins serving as signaling molecules
1. Relay proteins2. Messenger proteins3. Adaptor proteins4. Amplifier proteins5. Transducer proteins6. Bifurcation proteins7. Integrator proteins8. Latent gene regulatory proteins
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Two kinds of molecule switch eventsPhosphorylation and GTP binding
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Signaling integration
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Intracellular signaling complexes enhance the speed, efficiency, and specificity
2 types: Preassembled vs. Assembled after stimulation
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Intracellular signaling complexes enhance the speed, efficiency, and specificity
2 types: Preassembled vs. Assembled after stimulation
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Binding domains for interactions between proteins and complex assembly
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Cells can be sensitive to subtle difference in environment
1. Multiple ligands are needed for one signaling molecule
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Cells can be sensitive to subtle difference in environment
2. Multiple ligated molecules are needed to be assembled to be functional
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Cells can be sensitive to subtle difference in environment
3. Positive feedback can enhance the response drastically
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Cells can adjust their sensitivity to stimuli by desensitization process
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Summary
• Typical signaling transduction pathway: 1. ligand-receptor, 2. gap junctions
• Different inputs, receptors, intracellular signaling network determine the ultimate response
• The importance of lifetime of molecules• Different steps of responses• The types of receptors: ion-channel-linked, G
protein coupled, enzyme-linked receptors• Intracellular signaling molecules, signaling switches,
signaling integration, signaling complex assembly, protein-protein binding modulus, signaling amplification, signaling desensitization