Receptor Mediated Endocytosis
? The major mechanism of vesicular transport between ER
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and Golgi.? Takes place in the regions of the membranes known as
coated pits
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? The coated pits has high concentration of protein
clarthrin and this mechanism of receptor mediated
endocytosis is the clarthin coated vesicle method
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? However there is another method in which the receptor
mediated endocytosis takes place without the clarthin
coated vesicles
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? The SNARE proteins helps in the later type of the
receptor
Some Types of Vesicles and Their Functions
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Vesicle
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FunctionCOPI
Involved in intra-GA transport and
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retrograde transport from the GA to the
ER
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COPIIInvolved in export from the ER to either
ERGIC or the GA
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Clathrin
Involved in transport in post-GA locations
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including the PM, TGN and endosomesSecretory vesicles
Involved in regulated secretion from
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organs such as the pancreas (eg, secretion
of insulin)
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Vesicles from the TGNThey carry proteins to the PM and are also
to the PM
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involved in constitutive secretion
Steps in a round of anterograde
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transport involving COPII vesicles
Steps in a round of anterograde transport
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involving COPII vesicles
? Step 1: Sar1 is activated when GDP exchanged for
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GTP and it becomes embedded in the ER membraneto form a focal point for bud formation.
? Step 2: Coat proteins bind to Sar1?GTP and cargo
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proteins become enclosed inside the vesicles.? Step 3: The bud pinches off, formatting a complete
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coated vesicle. Vesicles move through cells alongmicrotubules or actin filaments.
? Step 4: The vesicle is
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uncoated when bound GTP is
hydrolyzed to GDP by Sar1.
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? Step 5: Rab molecules are attached to vesicles afterswitching of Rab.GDP to Rab.GTP, a specific GEF
.Rab effector proteins on target membranes bind to
Rab?GTP, tethering the vesicles to the target
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membrane.? Step 6: v-SNAREs pair with cognate t-SNAREs in
the target membrane to form a four helix bundle
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which docks the vesicles and initiates fusion.? Step 7: When the v- and t-SNARES are closely
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aligned, the vesicle fuses with the membrane and thecontents are released.
GTP is then hydrolyzed to GDP, and the Rab?GDP
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molecules are released into the cytosol.An ATPase (NSF) and -SNAP dissociate the four-
helix bundle between the v- and t-SNARES so that
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they can be reused.? Step 8: Rab and SNARE proteins are recycled for
further rounds of vesicle fusion
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Selective transport of proteins to lysosomes? The
best-characterized
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?These phosphorylated mannose
pathway of protein sorting in
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residuesare
specifically
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the Golgi is the selective
recognized by a mannose-6-
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transport of proteins tophosphate receptor in the trans
lysosomes.
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Goligi network
? Protein
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destinedfor
incorporation into lysosomes
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are modified by mannosephosphorylation.
? This occurs while the protein
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is still in the cis Golginetwork.
The M-6-P pathway
? In the trans-Golgi network, the phosphorylated
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enzymes bind to M6-P receptors .
? Which direct the enzymes into vesicles coated with
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the fibrous protein clathrin.? The clathrin lattices is rapidly depolymerized to its
subunits, and the uncoated transport vesicles fuse
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with late endosomes.? Within this low pH compartment, the phosphorylated
enzymes dissociate from the M6P receptors and then
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are de-phosphorylated.--- Content provided by FirstRanker.com ---
Targeting to lysosomes
I-cell disease
? Mucolipidosis II
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? UDP-N -acetyl glucosamine phosphotransferase? Cultured fibroblasts-deficient in numerous lysosomal
enzymes
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? Inclusions in lysosome? These enzymes were found to be present in excess in
tissue culture media and in extracellular fluids
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? Psychomotor and skeletal defectsBotulinum Toxin
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? Most lethal toxin known
? Most serious cause of food poisoning
? One component of the toxin is a protease specific
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only to the synaptobrevin? Thus by inhibiting the v-SNARE the release of
acetylcholine into the NMJ is halted
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Brefeldin ?A? An anti viral produced by fungus Penicillium
brefeldianum
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? Prevents GTP from binding to ARF in the step
1 of the anterograde pathway that Is the step of
Coat assembly
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? So in the presence of this fungal metabolite
the golgi apparatus appears to disintegrate and
fragments are lost
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Disorders Related to Intracellular TransportFamilial Hypercholesteremia
? Familial hypercholesterolemia, FH (type II
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hyperlipoproteinemia) is an autosomal dominant
disorder
? Results from mutations affecting the structure and
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function of the cell-surface receptor that binds plasma
LDLs (low density lipoproteins) removing them from
the circulation
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? The defects in LDL-receptor (LDLR) interactionresult in lifelong elevation of LDL-cholesterol in the
blood
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1. Receptor null mutation ( lack of receptor synthesis
in the ER
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2. Defective intracellular transport to golgi apparatus3. Defective extracellular ligand binding
4. Defective endocytosis
5. Failure to release LDL molecules inside the
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