Block2 3.receptor-Mediated Endocytosis

Front 1

Lysosomal Acid Hydrolases

Back 1

Acid hydrolases diverse group of enzymes. Act only at low pH's.

Front 2

Pathways Delivering Material to the Lysosome

Back 2

1. Endocytosis (receptor-mediated, many times clathrin coated pits are the site of invagination) or pinocytosis (cell drinking, non-specific)
2. Phagocytosis (macrophages and neutrophils) involves evagination out and around large particles like bacteria
3. Autophagy consuming one's self - damaged organelles, state of starvation
4.Protein signal KFERQ

Front 3

Events After Receptor-Mediated Endocytosis

Back 3

1. Clathrin rapidly removed, recycled to plasma membrane
2. Vesicle gains other proteins, particularly ATPase H+ pump to make vesicle acidified and acid hydrolases. This makes the vesicle a late endosome or lysosome
3. Ligand-receptor complex dissociate in the low pH

Front 4

Dynamin

Back 4

A GTP-dependent protein that serves to pinch off the vesicle as it invaginates with endocytosis

Front 5

Components of Coated Vesicles

Back 5

Clathrin, AP protein, receptors (enbedded in AP coat, NOT clathrin coat proteins), soluble cargo proteins

Front 6

Membrane Receptors

Back 6

Transduce signals across membrane.
1. Single pass = LDL, transferrin, growth factor receptors (growth factor receptors are NOT recycled, the others are)
2. 7-transmembrane region receptors = G-protein-coupled receptors

Front 7

Structure of LDL particle and receptor. NPXY sorting signal. Apolipoprotein B

Back 7

pH-dependent binding mechanism.
At the cell surface, the pH is neutral and the arm of the receptor binds the ligand on the LDL particle: Apolipoprotein B. The cytosolic portion of the membrane contains the NPXY sorting signal (allows
 movement of particles from
 plasma membrane interacting
 with AP2 to lysosome) Endocytosis occurs, and as the vesicle matures, the pH drops. At low pH the arm of receptor releases the LDL particle. Receptor recycles and the LDL is digested into basic components of amino acids, cholesterol, and fatty acids

Front 8

Hypercholestrolemia (familial hypercholesterolemia)

Back 8

Heterozygous – LDL ~2X elevated in blood
b. Homozygous – LDL 4X-6X elevated
c. Atherosclerotic plaques 10 years earlier (or more)
b. Premature heart attacks (as early as 20s)

Front 9

Internalization of Transferrin Receptor (Iron receptor), ferrotransferrin vs. apotransferrin

Back 9

Ferrotransferrin (with Fe3+) binds the Transferrin receptor at neutral pH outside cell. As the vesicle internalizes, the pH lowers, this causes release of the Fe from transferrin, resulting in apotransferrin (no Fe attached). It turns out that at low pH, the transferrin receptor prefers apotransferrin, so they stay bound together until the vesicle returns to the plasma membrane where the apotransferrin is released because the receptor once again prefers ferrotransferrin

Front 10

Internalization / Degradation of Membrane Receptors

Back 10

Membrane itself must be broken down while breaking down the integral proteins. It is an important process for breaking down membranes, which must be done

Front 11

Inward Budding of Multivesicular Body, HRS, ESCRT

Back 11

The HRS proteins and the proteins for degradation become MONOubiquinated. Once the HRS proteins are monoubiquinated, they can interact with ESCRT complex to induce invagination of a vesicle. The Vps4 protein recycles ESCRT via ATP hydrolysis. The vesicle and its receptors may then be broken down

Front 12

Retroviral outward budding

Back 12

The same process is utilized by HIV except the budding is outward out of the plasma membrane. The Gag protein is analogous to the HRS protein.