Week 7: Friday Flashcards
Cause of familial hypercholesterolemia
Mutations in the LDL receptor
What does the cytoplasmic tail of the LDL receptor interact with?
The cytoplasmic tail of the LDL receptor contains an endocytosis signal.
It binds to an adaptin in clathrin-coated pits.
ARH
Autosomal recessive hypercholesterolemia. This is the adaptin that binds the receptor tail.
Receptor mediated endocytosis
The process by which ARH and AP-2 work together ot endocytose LDL into CCVs.
Three types of LDL mutants
- LDL receptor mutants that did not fold properly and were retained in the ER.
- LDL receptor mutants that were transported normally to the plasma membrane, but could not bind LDL (binding site mutants).
- The third class was represented by a single patient “JD”, whose LDL receptor was transported normally to the plasma membrane, bound LDL normally, but failed to get endocytosed.
How is LDL internalized?
LDL is internalized by receptor mediated endocytosis.
Where is the LDL receptor with bound cargo transported to?
An early endosome.
Effect of acidic pH on the LDL receptor
The acidic pH of the early endosome causes receptor dissociation and LDL is dropped off in the lumen.
What happens to the protein component of LDL?
The protein component of LDL is degraded, cholesterol is transported out of the lysosome and sent to the ER.
Herceptin
Herceptin is a monoclonal antibody that recognizes the human epidermal growth factor receptor 2 (HER2) and is used to treat women with HER2-positive breast cancer.
What type of receptor is EGFR?
A tyrosine kinase
What happens when EGFR binds to EGF?
When EGFR binds EGF the receptor dimerizes, becomes activated and phosphorylates itself.
What happens after EGFR is phosphorylated?
The phosphorylated receptor recruits a RasGEF (Grb2-SOS) to the membrane that activates Ras (RasGDPRasGTP), which activates a cascade of protein kinases. EGFR also activates PI3K (both directly and because RasGTP stimulates PI3K activity). The downstream kinases drive gene expression changes that promote cell division.
Modification made to activated EGR receptor and effect
Activated EGR receptor is ubiquitinated and this modification serves as an endocytosis signal (recognized by a co-adaptor with AP-2
Fate of ubiquitinated plasma membrane proteins (such as the EGF receptor)
Ubiquitinated plasma membrane proteins (such as the EGF receptor) are endocytosed and sorted into the multivesicular body.
Two roles of ubiquitin
Ubiquitin can serve as both an endocytosis signal and MVB sorting signal
Effect of a failure to sort EGFR into the lumenal vesicles
A failure to sort EGFR into the lumenal vesicles allows recycling of the active receptor back to the plasma membrane (a pro-oncogenic situtation).
MVB pathway
Vesicles bud into the lumen of the organelle instead of budding into the cytosol.
How does HIV interact with the ESCRT complex?
HIV borrows the MVB machinery (ESCRT complex) in order to bud viral particles from the plasma membrane
Structure of ESCRT III
ESCRT III forms spiral structures that somehow forces the membrane to bud outwards.
How do many viruses enter the cell?
Many viruses, like influenza H1N1, use receptor-mediated endocytosis to enter cells
How is the flu virus internalized into the cell?
- The flu virus binds to cell surface glycoproteins bearing sialic acid on their N-linked oligos.
- The virus is internalized by endocytosis.
- The viral coats will then fuse with the endosome membrane to deposit the viral genome into the cytosol.
What type of process makes synaptic vesicles?
Synaptic vesicles are made through a clathrin-mediated endocytosis
How are synaptic vesicles regenerated?
Vesicles are regenerated by clathrin and refilled by the combined action of the V-ATPase and neurotransmitter/H+ antiporter
Kiss and run hypothesis
The synaptic vesicle may not completely fuse to the plasma membrane – In this hypothesis, the fusion pore opens transiently to allow neurotransmitter release and then close back up and the vesicle is release back to the cytosol.
What type of protein plays a role in pinching off synaptic vesicles?
Dynamin
