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Cell Biology Lecture No. 6.docx

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Biology 2382B
Sashko Damjanovski

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. 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. Pinocytosis is where small droplets of extracellular fluid and any material dissolved in it are non- specifically taken up. 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 adaptor protein (AP) complex 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: A short C-terminal cytosolic segment (with sorting signal), a long N-terminal exoplasmic segment (with a ligand-binding domain) 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 disassociated 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 passively follow the pumped protons resulting in acidifi
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