Cell Biology Lecture No. 6: Receptor-Mediated Endocytosis
th
Monday January 28 , 2013
LECTURE 5 CONT’D
Lysosomal Storage Diseases:
• -Lysosomal storage diseases are caused by the absence of one or more lysosomal
enzymes resulting in the accumulation of undegraded material in lysosomes.
• One of the most severe types of lysosomal storage disease is inclusion-cell (I-cell)
disease.
• It is caused by the absence of N-acetylglucosamine (GlcNAc) phosphotransferase,
which is required for phosphorylating enzymes bound for the lysosome (that carry the
M6P signal).
• Thus, lysosomal enzymes are secreted rather than being sorted to the lysosomes,
resulting in undigested glycolipids (normally degraded by lysosomal enzymes)
accumulating in the lysosomes.
• Lysosomal storage diseases typically have a fatal outcome early on in childhood.
LECTURE 6
Cells Internalizing Extracellular Materials:
• Cells internalize extracellular materials through three different types of endocytosis.
o Phagocytosis is a process by which relatively large particles (e.g. bacterial cells)
are internalized by certain eukaryotic cells that involves extensive remodeling of
the actin cytoskeleton.
o Pinocytosis is where small droplets of extracellular fluid and any material
dissolved in it are non-specifically taken up.
o Receptor-mediated endocytosis a where a specific receptor on the cell surface
binds tightly to an extracellular macromolecular ligand that it recognizes and the
plasma membrane region containing the receptor-ligand complex then buds
inward and pinches off, becoming a transport vesicle.
Molecules involved with receptor-mediated endocytosis include LDL
cholesterol, transferrin, hormones, and glycolipids.
Low-Density Lipoprotein (LDL): • Low-Density Lipoprotein (LDL) is a class of lipoprotein that has an amphipathic shell
(composed of a phospholipid monolayer, cholesterol and protein) with a hydrophobic
core (mostly cholesteryl esters) as the general structure.
• Although similar to other lipoprotein classes, LDL is unique in that it contains only a
single molecule of one type of apolipoprotein (ApoB), which appears to wrap around
the outside of the particle as a band of protein.
• Receptors in the plasma membrane recognize LDL as a unique ligand. Clathrin-coated
pits help to internalize LDL into the cell.
Clathrin & AP-Coated Vesicles:
• After a vesicle bud forms, dynamin polymerizes over the neck.
• By a mechanism that is not well understood, dynamin-catalyzed hydrolysis of GTP leads
to the release of the vesicle from the donor membrane.
• Note that the vesicles form a two layer coat of
o adaptor protein (AP) complex
o And fibrous clathrin.
• Membrane proteins in the donor membrane are incorporated into vesicles by interacting
with AP complexes in the coat (those being AP2 as the trans-Golgi network uses AP1
complexes in the coat).
PH-Dependent Binding of LDL Particles To LDL Receptor:
• The LDL Receptor (LDLR) has three domains:
o A short C-terminal cytosolic segment (with sorting signal),
o A long N-terminal exoplasmic segment (with a ligand-binding domain)
o And β-propeller domain.
• At neutral pH, the ligand-binding arm binds tightly to ApoB.
• At acidic pH (within the endosome), histidine residues in the β-propeller domain become
protonated and bind with high affinity to the negatively-charged residues in the ligand-
binding arm.
• This acts as a signal to disassociate from the LDL particle from its receptor.
Targeting LDL & LDL Receptors To Clathrin & AP2-Coated Pits: • Specific sorting signals (four-residue motif NPXY) within the cytosolic segment of
receptors binds to the AP2 complex.
• Together, the two kinds of coat proteins (clathrin and AP2) promote invagination of the
plasma membrane.
• It is at this point that ApoB mediate binding to the LDL receptor (ligand-binding domain).
Acidification Of Endosomes & Lysosomes:
• In late endosomes and lysosomes, v-class proton pumps work to transport H+ across
membranes via an ATP- dependent mechanism.
• Chloride channels are also present on the lysosomal and late endosomal membranes.
• These anions passi
More
Less
