15. vesicular, targeting lysosomes and endosomes Flashcards Preview

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1

destination tags

sending the transport vesicles to the correct destination

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destination tags four steps:

1. movement of the vesicles
2. tethering of vesicles
3. Docking
4. Membrane fusion

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destination tag step 1:

movement of the vesicles - on the microtubule component of the cytoskeleton

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destination tag step 2

tethering of vesicles to the target compartment is a specific recognition step.
-mediated by Rab proteins. A family of 6 different integral membrane proteins each specifying a target
*Rabs are GTP-binding proteins
-extended fibrous proteins called " tethering proteins "

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destination tags step 3:

Docking-the vesicle membranes become closely aligned-accomplished by the SNARE proteins: a family of 35 different proteins, each with different location/target
a)t-SNARES are target snares located on the receiving membrane- different ones on each different target membrane
b)v-SNARES are located on vesicle
-these are incorporated in the membrane during budding. the type of v-SNARE incorporated is determined by the vesicle protein type (type of COP)

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destination tags step 4:

membrane fusion-a second function of the snares
-the t and v SNARES helices intertwine and pull membrane together
example:
-synaptic vesicles dock to the pre-synaptic membrane in nerve cells
-2 t-SNARES:syntaxin, SNAP25
-single V-SNARE: synaptobrevin
-they all work together to link the vesicle to the presynaptic membrane, fusion, neurotransmitter release
-SNARE proteins are unraveled by a cytosolic protein=NSF

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SNARE proteins

direct vesicle traffic from one (specific) membrane to specific target
go to page 5

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Lysosome

-cells digestive organelle
-surrounded by a membrane
-contains~50 different hydrolytic enzymes
-these enzymes break down almost every known organic substance:
*nucleic acids
*proteins
*GAGs
*glycogen
*oligosaccharides
*sphingolipids
*phospholipids
*triglycerides

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the making of lysosomes

*proteins (enzymes) destined for lysosomes are "tagged" with phosphorylated mannose residues
*mannose 6-phosphate receptors (MPRs) collect these enzymes into budding vesicles
*another coat protein-clathrin-facilitates the vesicles budding
*Clathrin is shed, allowing this vesicle (sometimes called primary lysosome) to bind to phagosomes or other vesicles to form a secondary lysosome

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lysosomes maintain an internal acidic pH

*lysosomal enzymes have optimal activity at an acid pH
-they are therefore called acid hydrolases
*lysosomal membrane contains:
-proton pump (H+-ATPase) to maintain acid pH inside
-2 groups of acidic, highly glycosylated integral proteins line the interior of the lysosome; these may protect membrane from enclosed enzymes

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4 functions of lysosomes

1. heterophagy
2. autophagy
3. autolysis
4. extracellular digestion

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Heterophagy

-degradation of foreign material brought into cell by phagocytosis (cell eating)
-primary lysosome fuses with phagosome and contents digested
*nutrition-products move into cytoplasm
*defence-microorganisms are killed
lysosome + phagosome= phagolysosome

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autophagy (self-eating)

-digestion of intracellular components that have damage or no longer needed
-isolation envelope forms around components to be removed
-fuses with primary lysosome and contents broken down
lysosome + autophagic vacuole = autophagolysosome

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Autolysis (cellular self-destruction)

-rupture of lysosome within cytoplasm kills the cell
-part of programmed cell death during development
-example is selective removal of cells leads to fingers and toes
*41 days post fertilization: webbing between fingers
*56 days post fertilization: webbing gone

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extracellular digestion

in rare cases, lysosome may discharge their enzymes to the outside of cell by exocytosis
e.g acrosome in sperm at fertilization

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Lysosomes gone bad

(ie they fail to do their job)
1. some phagocytosed bacteria escape being killed
2. lysosomes with a missing acid hydrolase

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some phagocytosed bacteria escape being killed

a) fusion of primary lysosome and phagosome is inhibited. bacteria responsible for tuberculosis can do this
b) secondary lysosome does not kill bacterium. bacteria responsible for Q fever are not killed by lysosomal enzymes
c) bacteria escape secondary lysosome. bacteria produce phospholipase to destroy lysosomal membrane. bacteria escape into cytosol or cytoplasm (eg. spotted fever rickettsia)

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lysosomes with a missing acid hydrolase

-these defective lysosomes are the cause of lysosomal storage diseases
- ~40 lysosomal storage diseases
-accumulation of excessive amount of specific substances
eg. tay-sachs disease

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Tay-Sachs disease

-accumulation of ganglioside (kind of glycolipid) in brains of afflicted children
-mental retardation and death by age 3

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enzyme replacement therapy:

intravenously injected enzyme may be taken up by cells in vesicles, which then can fuse with lysosomes to replace missing enzyme

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endocytosis

cellular uptake of particles and macromolecules

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3 mechanisms of endocytosis:

1. phagocytosis-uptake of particulate matter
2. pinocytosis - cell 'drinking' - size matters in terms of what we call drinking vs eating
3. receptor mediated endocytosis- uptake of specific molecules

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Phagocytosis

-cell eating
*uptake of particulate material and delivery to a lysosome
*enclosed in phagosome
-phagosome fuses with primary lysosome
*protective mechanism in higher animals
*macrophages and neutrophils are professional phagocytes
-cells have lysosomal mechanisms for killing ingested microorganisms:

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phagocytosis
cells have lysosomal mechanisms for killing ingested microorganisms:

1. contain lysozyme, an enzyme that degrades bacterial cell walls
2. acidic pH kills some
3. oxidases on inner surface of phagosome produce hydrogen peroxide that kills some bacteria

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endocytosis 2 categories:

1. bulk-phase endocytosis
2. receptor-mediated endocytosis

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bulk-phase endocytosis

-brings about uptake of extracellular fluids without recognition by surface of plasma membrane
-any molecules that happen to be present in enclosed fluid gain entry into cells
-occurs in a continual manner in many types of cells

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receptor-mediated endocytosis

-brings about uptake of specific macromolecules (ligands) following their binding to receptors on plasma membrane
-material taken up by endocytosis is delivered to a network of tubules and vesicles
-these are collectively known as endosomes

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endosomes

-network of cytoplasmic membrane vesicles and tubules
-early endosomes are located near peripheral region of cell
-late endosomes are in interior part of cell
*late endosomes receive material from early endosomes and golgi apparatus
-some late endosomes can be thought of as a pre-lysosomal compartment

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Coated pits

sites on membrane where receptors for receptor-mediated endocytosis are concentrated
-surface first becomes indented
-indentation is covered on its cytoplasmic side y a layer of proteins known as the clathrin coat

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endocytosis pathway

1. clathrin coat is removed from coated vesicle to yield uncoated vesicle
2. uncoated vesicle fuses with early endosome
3. transport of carrier vesicle buds off from early endosome
4. transport vesicle fuses with late endosome
5. transport vesicles bud off from late endosome and contain either:
a) ligand
b) receptor only
c) receptor-ligand complex