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Previously Bio308

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

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Previously Bio308

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  1. 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

  2. Lumenal proteins Single transmembrane span proteins Multipass transmembrane proteins ER proteins ER Where can a protein end up in the ER? How does it get there? What category do our neurotransmitter and neurotransmitter receptor fall in?

  3. How do you get soluble lumenal proteins vs ‘Type III’ What’s different? How does it happen?

  4. Golgi enzyme involved in glycosylation Neurotransmitter receptor Lysosomal acid hydrolase Getting out of the ER ER Now what?

  5. Vesicular traffic Secretory pathway: also method for delivering new PM proteins ER to Golgi to trans-Golgi network  then constitutive or regulated exocytosis

  6. Constitutive and Regulated Exocytosis Constitutive= constant, sometimes called ‘bulk flow’ Constitutive does not mean ‘un-regulated’ Regulated= needs additional signal to initiate fusion of vesicle with PM

  7. Donor Donor Target Target Stages of vesicle traffic 3 Stages: Budding, targeting/docking and fusion

  8. 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

  9. 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?

  10. Content selection What goes inside which vesicle? Lumenal protein: Transmembrane proteins: Combination of cytosolic and lumenal proteins determine specific vesicle content

  11. http://biology-animations.blogspot.com/2009/10/clathrin-animation.htmlhttp://biology-animations.blogspot.com/2009/10/clathrin-animation.html Budding Fig 17-58

  12. 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

  13. 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 Budding II ER vesicle budding Sar1p N-terminal helix Amino Acid Key Drin, G, and B. Antonny (2005) News and Views: Helices sculpt membrane. Nature vol: 437

  14. 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

  15. ER vesicle budding….fission 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

  16. 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

  17. The SNARE hypothesis V-SNARE T-SNARE Role of p115 Role of Rab proteins retrograde Fig 17-59

  18. Synaptic vesicle fusion VAMP Syntaxin SNAP 25 Rab3a Synaptotagmin

  19. 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?)

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