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Download Getting things where they need to go: Protein Targeting
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Transcript
Previously Bio308 Hypotheses for molecular basis of bipolar disorder •Suggest problem lies in protein targeting How are proteins targeted and delivered? Sorting places proteins in membrane and in lumen of organelles PM (and other) proteins use Sec or SRP mediated translocation to become inserted into the ER (and only the ER) After insertion non-ER proteins are sorted and delivered sorting lumenal vs membrane proteins –how? http://www.udel.edu/Biology/Wags/histopage/empage/ebv/ebv10.gif Stages of vesicle traffic 3 Stages: Budding, targeting/docking and fusion Donor Donor Target Target Consequences of unregulated vesicular traffic Mixing of organelle contents ( won’t function correctly) Mislocalization of proteins ( won’t function correctly) Inappropriate levels of secretion (too hi or too lo) A Dead Cell Vesicular traffic control Our neurotransmitter receptor need to go ‘through’ 5 cellular compartments before it gets to the post synaptic membrane How does a vesicle ‘know’ what components it should contain? How does it ‘know’ which membrane it should go to? How does it fuse when it gets there? Content selection What goes inside which vesicle? Lumenal protein: Transmembrane proteins: Combination of cytosolic and lumenal proteins determine specific vesicle content Budding Fig 17-58 CBI 13.1 Clathrin Coat Components Clathrin COPI COPII Identity determined by what the vesicle contains and it’s coat. http://userpage.chemie.fu-berlin.de/biochemie/aghaucke/clath.jpg Budding II ER vesicle budding Sar1p N-terminal helix Amino Acid Key Highly hydrophobic + charged - charged Hydroxylated Other Sar1p-GTP form exposes helix that anchors protein to ER surface by ‘floating’ with hydrophobic a.a. interacting with membrane core Drin, G, and B. Antonny (2005) News and Views: Helices sculpt membrane. Nature vol: 437 Budding III ER vesicle budding Floating many Sar1p in top leaflet makes it ‘bigger’ than the bottom one. Results --> bulge that can more easily interact with coat proteins. Drin, G, and B. Antonny (2005) News and Views: Helices sculpt membrane. Nature vol: 437 Fission ER vesicle budding….fission Ring of parallel helices at neck might aid fission. New data for ER; had seen a protein (epsin) help deform PM for clathrin coated vesicles. May suggest that using a helix to deform membrane is common mechanism for budding/fission Targeting/Docking: What happens after budding? How do vesicles dock with specific target membrane? http://dir2.nichd.nih.gov/nichd/cbmb/sob/in_vivo_dyn.html The SNARE hypothesis V-SNARE T-SNARE Role of p115 Role of Rab proteins retrograde Fig 17-59 Synaptic vesicle fusion VAMP Syntaxin SNAP 25 Rab3a Synaptotagmin Next: Moving in the other direction: endocytosis Types: Phagocytosis– specialized cells Pinocytosis– all cells Connection– perhaps the # of our receptor’s on PM is controlled by endocytosis Pinocytosis ‘problem’ rate of pinocytosis internalizes 100% of PM per hour ? (How can this be?)
