L8: Membrane trafficking II part 3 Flashcards
(9 cards)
changes to the endosome upon maturation
Changes to the endosome upon maturation
Vesicles fuse together to form the early endosome. ?
A H+ ATPase in endo- and
lysosomal membranes
acidifies the lumen
Rab5 (early endosome) is
replaced by Rab7 (late
endosome) – identity change
lysosomes
A mannose 6-phosphate (M6P) is added to hydrolases in the Golgi
* A M6P receptor (MPR) packages hydrolases into vesicles budding
from Golgi and transports them to endosomes.
* At the acidic endosomal pH, hydrolases dissociate from MPR
nutrient uptake
The endosomal network allows nutrient uptake: cholesterol
Endocytic network needed to internalise nutrients. Cholesterol from food or made in liver. Necessary to have but bad if too much. Transported in its esterified form by low-density lipoproteins (LDL). esterified bags of cholesterol form from phospholipids, travel in blood and internalise in cells with LDL receptors.
Presentation of LDL-R allows uptake of LDL
LDL floating in extracellular space. On surface of cells have LDL-R that bind LDL. LDL-R bind adaptor proteins that bind to clathrina nd cause sequestration of LDL and LDL-R in clathrin coated pits. LDL-Receptor C-terminus has an NPXY sequence for binding the
clathrin adapter protein AP-2
So allows incorporation in clathrin coated vesicle.
Vesicle coated and fuses with endosome. As endosome acidifies, LDL degraded. So by the time ldl gets to lysosome, degradation happens alot and cholesterol released from the lyososme. Empty LDL-R recycled back to the pm to pick up more LDL from the outside world.
A patient mutation in the LDL-R causes
familial hypercholesterolaemia
- Genetic mutation of NPVY to NPVC: Can’t engage uptake machinery
- Identified in patient JD – familial hypercholesterolaemia
- Nobel prize (1985) Brown and Goldstein
Removes one residue from this recognition sequence for the adaptor protein. Stops LDL-R binding to clathrin-adaptor complex so LDL-R not internalised and LDL cant be brought into cell. Elavayed levels of low density lipoproteins in ECF. causes hypocholestolaeia.
(Defective coated pit binding site)
Prevents clathrin dependent internalisation of this molecule.
How do statins work?
how do statins work
Drugs that lower cholesterol.
HMG CoA-reductase
inhibitors
* Prevent de-novo
cholesterol synthesis
* Body has to upregulate
LDL-R to extract
cholesterol from blood
* Circulating levels of LDL
drop – reduced risk of
artherosclerosis
cellular uptake of iron
- Iron is transported in
the blood bound to
transferrin - Transferrin can be Apo
(empty) or Iron bound - Transferrin binds iron
at neutral pH and
releases it at acidic pH - Iron released from
endosomes via a pH
sensitive ion channel
(DMT1)
signalling GF receptors
Signalling GF-receptors are degraded in lysosomes, rather than being recycled
* LDL-Receptors Internalise constitutively: Recycled
* Transferrin-R Internalise when Tfn bound: Recycled
* EGF-Receptors Internalise when EGF bound: Degraded
* Lysosomal sorting after internalization results in a reduction in
receptor number: receptor downregulation
* Curtails signaling, reduces receptor number, prevents recycling
Important for downreg/desensitiation to reduce sensitivity of cells to a stimulus once they experienced it.
ensuring receptor degradation
Ensuring receptor degradation
* If cargo can recycle from endosomes, how does the cell ensure
cargo that needs to be degraded ends up in the lysosome?
* Cargo that is to be degraded is
ubiquitinated
* Endosomal proteins called ESCRTs
bind ubiquitinated cargo to retain it
* ESCRT proteins make the endosome
involute to make intra-endosomal
vesicles
* The cargo to be degraded is trapped
late endosome
The late endosome is also known as a multivesicular body (MVB)
* Late endosomes fuse directly with lysosomes to degrade
endosomal content on intraluminal vesicles
Escrt machinery works on the limiting membrane of an endosome cause a budding and cargo sequestration into the endosomal lumen forming endosomal vesicles. Late endosoemes fuse directly with lysosomes to deliver content to the lysosomal lumen for degradation.
other pathways that converge on lysosomes
Other pathways that converge on lysosomes
While endocytosis makes late endosome that fuses with lysosome for degradation, Lysosomes degrade not only content from the endosomal system, but will destroy
phagocytosed bacteria and autophagic vacuoles too where cell chooses to sequester its own cytoplasm and organelles in a membrane bound structure: autophagosome which fuses with the lyososme so content is degraded.
