previously bio308
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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 - PowerPoint PPT PresentationTRANSCRIPT
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Previously Bio308
Hypotheses for molecular basis of bipolar disorder•Suggest problem lies in protein targetingHow 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 tobecome inserted into the ER (and only the ER)
After insertion non-ER proteins are sorted and deliveredsorting lumenal vs membrane proteins –how?
http://www.udel.edu/Biology/Wags/histopage/empage/ebv/ebv10.gif
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Stages of vesicle traffic
3 Stages: Budding, targeting/docking and fusion
DonorDonor
Target
Target
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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
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Vesicular traffic control
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?
Our neurotransmitter receptor need to go ‘through’ 5 cellular compartments before it gets to the post synaptic membrane
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Content selection
What goes inside which vesicle?
Lumenal protein:
Transmembrane proteins:
Combination of cytosolic andlumenal proteins determinespecific vesicle content
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Budding
Fig 17-58 CBI 13.1 Clathrin
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Coat Components
http://userpage.chemie.fu-berlin.de/biochemie/aghaucke/clath.jpg
ClathrinCOPICOPII
Identity determined by whatthe vesicle contains and it’s coat.
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Budding IIER vesicle budding
Drin, G, and B. Antonny (2005) News and Views: Helices sculpt membrane. Nature vol: 437
Amino Acid Key
Highly hydrophobic
+ charged - charged
Other
Hydroxylated
Sar1p N-terminal helix
Sar1p-GTP form exposes helix that anchors protein to ER surface by‘floating’ with hydrophobic a.a. interacting with membrane core
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Budding III
Drin, G, and B. Antonny (2005) News and Views: Helices sculpt membrane. Nature vol: 437
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.
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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
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Targeting/Docking:
http://dir2.nichd.nih.gov/nichd/cbmb/sob/in_vivo_dyn.html
What happens after budding?
How do vesicles dock with specific target membrane?
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The SNARE hypothesis
Fig 17-59
V-SNARE
T-SNARE
Role of p115Role of Rab proteins
retrograde
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Synaptic vesicle fusion
VAMP
SyntaxinSNAP 25
Synaptotagmin
Rab3a
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Next: Moving in the other direction: endocytosisTypes: 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?)