Flashcards in M&R 6.2 - Receptor Mediated Endocytosis Deck (25):
What is receptor mediated endocytosis?
The selective internalisation of molecules due to activation of specific receptors
What is the mechanism for endocytosis?
- Cell surface membrane of the vesicle fuses with the cell surface membrane of the cell
- Both membranes merge therefore releasing the molecule
Describe the structure of a low density lipoprotein
- Hydrophobic core made from: Triacylglycerols and cholesterol esters
- Surface coat made from: phospholipids, cholesterol and Apoprotein B
What kind of receptor do cells that require cholesterol synthesis? Where are these receptors located?
- LDL receptors that specifically recognise apoprotein B
- Located directly over Clathrin Coated Pits (cover ~2% of the cell surface)
What happens when LDL binds to the receptors?
- Pit invaginates which encases the receptor and the LDL
- Then uncoats using energy from ATP
- Fuses with large, smooth vesicles (endosomes)
What is an endosome?
A compartment for the uncoupling of the receptor and the ligand (CURL)
What is the significance of the endosome having a lower pH than the cytoplasm? How is this maintained
- Decreases the affinity of the LDL receptor for the LDL which causes them to dissociate
- Maintained by the ATP dependent H+ pump
What happens to the receptor once it has dissociated from the LDL?
- Moves into a separate area of the endosome
- Buds off
- Recycled to the plasma membrane
What happens to the LDL once it has dissociated from the receptor?
- Endosome containing the LDL fuses with a lysosome
- Lysosome hydrolyses LDL
- Releases free cholesterol to the cell (along with esters)
Describe 3 mutations that can cause hypercholesterolaemia
- LDL receptors aren't above clathrin coated pits (cover entire surface rather than 2%) due to a deletion at the c-terminal - causes no interaction
- Mutation to receptor binding site = no LDL uptake
- Receptor deficiency due to mutation = less LDL uptake
How is transferrin formed in circulation?
- 2x Fe3+ bind to Apotransferrin = Transferrin
How is transferrin brought into the cell?
- Binds to a high affinity transferrin receptor on CSM
- Take in similarly to LDL (coated pit, then uncoated and fuses with endosome)
- pH competes for binding with transferrin which causes Fe3+ to be released (used with Hb)
- Apoferrin has a high affinity for the receptor at a lower pH so stays bound
What happens to the transferrin receptor after dissociation?
- Recycled to the plasma membrane
- Apoferrin is released when pH returns to 7
How does RME differ with insulin receptors? Why?
- The receptors ONLY congregate over the Clathrin coated ONCE THE AGONIST HAS BOUND
- Binding causes a conformational change that allows receptor to be recognised by the pit
What happens to the insulin-receptor complex when in the endosome?
- Remains bound
- Targeted by lysosomes for degradation (receptor and insulin are degraded so receptor isn't recycled)
What is the significance of uptake of occupied insulin receptors?
- Reduces number of insulin receptors on CSM
- Desensitised to the constant high concentration of insulin in circulation
Describe the development of type 2 diabetes
- Increased blood glucose levels means more insulin is secreted by beta cells
- Causes a down regulation of receptors (= resistance) which decreases the response to insulin
- Decreases glucose uptake so more is produced by the liver = HYPERGLYCAEMIA
- Less glucose transport, more insulin resistance
- Coupled with impaired beta cell function
- Resistance + deficiency = Type 2 diabetes
What is transcytosis?
Transport of ligand + receptor ACROSS THE CELL
Give 2 examples of transcytosis
- Maternal immunoglobulin to the foetus via the placenta
- Immunoglobulin A (IgA) from the circulation to bile in the liver
What is the affect of pH on IgA
- Has no effect
- Budding off of vesicle contains both receptor & ligand
What happens during the transport of IgA to the bile?
- Happens in a transfer vesicle (still bound)
- Proteolytic cleavage of the receptor leaves a small amount of the receptor bound to the ligand (secretory component)
Which method is used by all mechanisms of RME?
- Compartment for the uncoupling of the receptor and the ligand (endosome)
How can RME be exploited by viruses/toxins?
- Binds to receptor and is internalised in the same way as a metabolite
- Lower pH of the endosome causes a conformational change of enveloping proteins therefore exposing hydrophobic domains
- Viral membrane can fuse with the endosomal membrane
What happens after the fusion of the viral membrane with the endosomal membrane?
- Virus releases its own RNA into the cell
- Cell replicates itself and viral RNA to form a new virus