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Cell Biology Lecture No. 6.docx

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Biology 2382B
Robert Cumming

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
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