Download MBBS (Bachelor of Medicine and Bachelor of Surgery) Latest Trafficking of Protein V Lecture PPT
Receptor Mediated Endocytosis
? The major mechanism of vesicular transport between ER
and Golgi.
? Takes place in the regions of the membranes known as
coated pits
? The coated pits has high concentration of protein
clarthrin and this mechanism of receptor mediated
endocytosis is the clarthin coated vesicle method
? However there is another method in which the receptor
mediated endocytosis takes place without the clarthin
coated vesicles
? The SNARE proteins helps in the later type of the
receptor
Some Types of Vesicles and Their Functions
Vesicle
Function
COPI
Involved in intra-GA transport and
retrograde transport from the GA to the
ER
COPII
Involved in export from the ER to either
ERGIC or the GA
Clathrin
Involved in transport in post-GA locations
including the PM, TGN and endosomes
Secretory vesicles
Involved in regulated secretion from
organs such as the pancreas (eg, secretion
of insulin)
Vesicles from the TGN
They carry proteins to the PM and are also
to the PM
involved in constitutive secretion
Steps in a round of anterograde
transport involving COPII vesicles
Steps in a round of anterograde transport
involving COPII vesicles
? Step 1: Sar1 is activated when GDP exchanged for
GTP and it becomes embedded in the ER membrane
to form a focal point for bud formation.
? Step 2: Coat proteins bind to Sar1?GTP and cargo
proteins become enclosed inside the vesicles.
? Step 3: The bud pinches off, formatting a complete
coated vesicle. Vesicles move through cells along
microtubules or actin filaments.
? Step 4: The vesicle is
uncoated when bound GTP is
hydrolyzed to GDP by Sar1.
? Step 5: Rab molecules are attached to vesicles after
switching 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
membrane.
? Step 6: v-SNAREs pair with cognate t-SNAREs in
the target membrane to form a four helix bundle
which docks the vesicles and initiates fusion.
? Step 7: When the v- and t-SNARES are closely
aligned, the vesicle fuses with the membrane and the
contents are released.
GTP is then hydrolyzed to GDP, and the Rab?GDP
molecules are released into the cytosol.
An ATPase (NSF) and -SNAP dissociate the four-
helix bundle between the v- and t-SNARES so that
they can be reused.
? Step 8: Rab and SNARE proteins are recycled for
further rounds of vesicle fusion
Selective transport of proteins to lysosomes
? The
best-characterized
?These phosphorylated mannose
pathway of protein sorting in
residues
are
specifically
the Golgi is the selective
recognized by a mannose-6-
transport of proteins to
phosphate receptor in the trans
lysosomes.
Goligi network
? Protein
destined
for
incorporation into lysosomes
are modified by mannose
phosphorylation.
? This occurs while the protein
is still in the cis Golgi
network.
The M-6-P pathway
? In the trans-Golgi network, the phosphorylated
enzymes bind to M6-P receptors .
? Which direct the enzymes into vesicles coated with
the fibrous protein clathrin.
? The clathrin lattices is rapidly depolymerized to its
subunits, and the uncoated transport vesicles fuse
with late endosomes.
? Within this low pH compartment, the phosphorylated
enzymes dissociate from the M6P receptors and then
are de-phosphorylated.
Targeting to lysosomes
I-cell disease
? Mucolipidosis II
? UDP-N -acetyl glucosamine phosphotransferase
? Cultured fibroblasts-deficient in numerous lysosomal
enzymes
? Inclusions in lysosome
? These enzymes were found to be present in excess in
tissue culture media and in extracellular fluids
? Psychomotor and skeletal defects
Botulinum Toxin
? Most lethal toxin known
? Most serious cause of food poisoning
? One component of the toxin is a protease specific
only to the synaptobrevin
? Thus by inhibiting the v-SNARE the release of
acetylcholine into the NMJ is halted
Brefeldin ?A
? An anti viral produced by fungus Penicillium
brefeldianum
? Prevents GTP from binding to ARF in the step
1 of the anterograde pathway that Is the step of
Coat assembly
? So in the presence of this fungal metabolite
the golgi apparatus appears to disintegrate and
fragments are lost
Disorders Related to Intracellular Transport
Familial Hypercholesteremia
? Familial hypercholesterolemia, FH (type II
hyperlipoproteinemia) is an autosomal dominant
disorder
? Results from mutations affecting the structure and
function of the cell-surface receptor that binds plasma
LDLs (low density lipoproteins) removing them from
the circulation
? The defects in LDL-receptor (LDLR) interaction
result in lifelong elevation of LDL-cholesterol in the
blood
1. Receptor null mutation ( lack of receptor synthesis
in the ER
2. Defective intracellular transport to golgi apparatus
3. Defective extracellular ligand binding
4. Defective endocytosis
5. Failure to release LDL molecules inside the
endosome
This post was last modified on 30 November 2021