Download MBBS Trafficking of Protein V Lecture PPT

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