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Lecture

Receptor Mediated Endocytosis.docx


Department
Biology
Course Code
BIOL 2382B
Professor
Jessica Kelly

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1
Lecture 6 Receptor Mediated Endocytosis
Internalizing Extracellular Material
Phagocytosis - process by which relatively large particles (e.g., bacterial cells) are
internalized by certain eukaryotic cells (i.e. phagoctyes of immune system) in a process
that involves extensive remodeling of the actin cytoskeleton
Pinocytosis not specific; it is the internalization of extracellular fluid that could contain a
variety of compounds and substances
Receptor-mediated endocytosis - method of selective internalization of specific
extracellular molecules (ligands)
Example:
LDL (low-density lipoprotein), transferrin, hormones (e.g. insulin), certain
glycoproteins, etc.
Low Density Lipoprotein (LDL)
Cholesterol (a fatty acid) can be
ingested and also produced in the liver
Lysosomes in cells digest cholesterol
for use in biosynthesis of cell structures
(i.e. generation and maintenance of cell
and intracellular membranes)
LDL particles are used to transport the
hydrophobic cholesterol through the
blood stream via use of a lipid
monolayer
Apolipoprotein B associates with LDL
particles by forming a band around
them
Apo B acts as a ligand for the LDL
receptor protein on the membranes of
cells
LDL receptors recognize ApoB and are
essential in endocytosis of LDL
Amphipathic shell - composed of a
phospholipid monolayer, apolipoprotein, and
cholesterol.
Apolar core hydrophobic, mostly
cholesteryl esters

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2
Vesicle Formation in Endocytosis
Binding of LDL Particles to LDLR is pH Dependent
Clathrin/AP-coated Vesicles
Two layer coat of an adapter protein
(AP) and clathrin complex
required to
physically pinch membranes into
vesicles
Cargo protein (transmembrane protein)
contains a signal sequence on the
cystolic face of the membrane that is
recognized by specific adapter proteins
Association of the AP is followed by
clathrin association causes the
physical pinching of the plasma
membrane
The neck portion of the pinching
membrane requires dynamin to
polymerize there and
hydrolyze GTP to
GDP
to completely pinch off the vesicle
LDLR has 3 Domains
Short C-terminal cytosolic segment
with sorting signal
Long N-terminal exoplasmic segment
with a ligand binding domain and β -
propeller domain
Normal pH (~7.0) = the ligand-binding
arm binds tightly to ApoB (which is
associated with LDL particle)
Acidic pH (5.0-5.5) = histidine residues in
β
-propeller domain become protonated and
bind with high affinity to the negatively
charged residues in the ligand-binding
arm
The pH determines how LDLR associated
with LDL particle…
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3
Targeting LDL and LDLR to Clathrin/AP2-coated Pits
Combined interactions of LDL particle with the ligand domain of LDLR and the
cytoplasmic interaction of AP2/Clathrin complex with LDLR result in formation of
LDL containing vesicles…
Acidification of Endosomes and Lysosomes
Specific sorting signals in the cytoplasmic
domain (a four-residue motif NPXY) of
LDL receptors bind to the AP2/Clathrin
complex (which recognize this motif).
ApoB mediates binding of LDL particle to
exoplasmic face of the LDL receptor
V-class proton pumps - transport H+ across
membranes via an ATP dependent mechanism
Cl- channels are also present on lysosomal and
endosomal membranes
Anions passively follow the pumped protons
resulting in acidification of lumen
The lowered pH within the lysosome or endosome
created by this pumping is required for LDL
particle dissociation from the LDL receptor…
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