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Functions of Golgi Apparatus

- sorting and dispatching station for proteins and lipids made in ER
- modification of N-linked oligosaccharide chains on glycoproteins made in ER
- synthesis of O-linked oligosaccharides on proteins and lipids made in ER
- synthesis of glycosaminoglycan chains on core proteins of proteoglycans

1

Structure of Golgi Appartaus

- flattened cisternae stacked together
- cis face (entry face) - adjacent to ER, sorts proteins going back to ER (ER retention signal)
- trans face (exit face) - pointing toward PM, sorts to lysosome and secretory vesicle (signal required), PM (default - no signal)
- usually located near the cell nucleus
- # Golgi stacks per cell varies by cell type

2

Modification of N-linked Oligosaccharides in Golgi

- sugar additions and removals (glycosidases and glycosyl transferases)
- 3 classes with varying degrees of modification: high mannose (little processing), complex (high processing), hybrid

3

O-linked Glycosylation of Proteins

- cov. attachement of oligosacchrides to OH groups of serine or threonine residues in proteins
- occurs in Golgi, post-translationally via glycosyltransferases
- sugars are added to proteins one at a time (O-linked = One) top build oligosaccharide directly on protein
-

4

Proteoglycan structure and function

- contain >95% carbohydrate by mass (diff. proteoglycans)
- carb chain always consists of glycosaminoglycan chains (very neg. charge 6 classes)
- attract water to form lubricants and gels and spring back when compressed
- synthesized in Golgi
- often found in animal extracellular matrix and on cell surfaces

5

Synthesis of proteoglycans

- core protein syn. in ER, transported to Golgi
- in Golgi, glycosyltransferases act sequentially to build 4 sugar linker on serine of core protein
- repeated action of 2 glycosyltransferases add sugars to chain, sugars modified as chain grows

6

Define: Glycoprotein

- any protein with one more covalently bound carb. units that do not contain a serial repeat
- mostly protein with a little carb (no glycosaminoglycan chain)
- most soluble/membrane proteins made in ER are glycoproteins

7

Define: Proteoglycan

- small core protein with one or more bound glycosaminoglycans, which consist of a repeating disaccharide
- mostly carb with little protein

8

Functions of glycoproteins

- extracellular matrix
- hormones
- lubrication and protection
- enzymes
- immunologic molecules
- cell surface antigens
- plasma proteins

9

Mucins

- special class of O-linked glycoproteins
~ 80% carb by mass (a lot for a glycoprotein)
- most abundant macromolecule in mucus that covers epithelial surfaces (resp., GI, genital tracts)
- form a hydrated gel
- protect epithelial cells from noxious substances
- provides lub. to minimize shear forces

10

ABO blood group antigens

- oligosacchride components of glycoproteins and glycolipids on surface of red blood cells
- extremely immunogenic
- important in transfusion medicine
- product of ABO gene locus determines if a sugar will be added to O to become either A (GalNAc added) or B (Gal added)

11

Blood Type O (OO)

- No A or B antigens on RBC (do not make either transferase)
- universal donor - donated to individuals with any blood type because no A or B antigen to be recognized by recipient's immune system

12

Blood Type A (AA or AO)

- A antigen on RBC (makes GalNAs transferase)
- donated to A or AB blood types
- recipients recognize A antigen as "self"

13

Blood Type B (BB or BO)

- B antigen on RBC (make only Gal transferase)
- donated to AB or B

14

Blood Type AB

- copy of GalNAc and Gal transferase
- A and B antigens on RBC
- donated only to type AB
- receive from any blood type (universal acceptor) - don't make antigens to either A or B antigen

15

Constitutive exocytosis pathway

- default pathway: all proteins going thru Golgi enter this pathway unless a specific signal directs them
- vesicles bud from trans Gogli, fuse with PM (supplies with newly made lipids/proteins)
- operates continually in all cells

16

Regulated exocytosis pathway (clathrin-coated vesicles)

- found in secretory cells (i.e. cells that secrete a lot of hormones or digestive enzymes)
- proteins in secretory vesicles, bud off from trans Golgi, fuse with PM
- release contents ONLY in response to an extracellular signal

17

Define: Endocytosis

- uptake of material at cell surface and delivery to lysosomes for digestion via endosomes

18

Define: pinocytosis

- aka endocytosis; "cell drinking"
- uptake of fluid and small molecules in small vesicles
- continuous process in all eukaryotic cells
- carried out by clathrin-coated pits and vesicles: Extracellular fluid trapped in pit is internalized and delivered to early endosomes

19

Define: phagocytosis

- uptake of large particle such as bacteria in large vesicles (phagosomes)
- requires receptor activation at cell surface
- occurs in specialized cells (macrophages and neutrophils)

20

Receptor-mediated endocytosis of LDL

- more efficient than ordinary pinocytosis
- when cholesterol is needed, cells syn./insert LDL receptors on PM
- receptor and LDL particles pulled in in clathrin-coated pits, vesicles shed coats and fuse with endosomes -> dissociation of LDL from receptor
- LDL -> lysosome -> hydrolyzed to free cholesterol -> released into cytosol for membrane syn.
- LDL receptor recycled to PM

21

Familial hypercholesterolemia

- defect in LDL receptor gene
- cholesterol uptake blocked so it accumulates in blood
- leads to plaque formation in blood vessel walls and xanthomas in skin and tendons

22

Early endosomes

- located near PM
- main sorting station in endocytic pathway
- endocytosed materials arrive within minutes
- low pH allows some receptors to release ligands - usually transported to lysosomes for degradation

23

Late endosomes

- located near nucleus
- basically "immature" lysosomes
- endocytosed materials arrive from early endosomes 5-15 min after uptake
- materials eventually transported to lysosome via vesicles or conversion to lysosomes

24

3 pathways of endocytosed materials

1. recycling: return to PM (ex. LDL receptors)
2. degradation: transport from early endosome to lysosome. Leads to decrease in receptor concentration -> receptor down regulation
3. transcytosis: return to different PM domain in polarized (basolateral membrane -> apical membrane)

25

Structure and function of lysosomes

- principal site of intracellular digestion (all euk. cells)
- contain ~40 acid hydrolases
- membrane has ATP-driven H+ pump that maintains pH 5 (optimal for hydrolases)
- membrane contain transport proteins (digestion products and nucleotides to cytosol)
- membrane proteins heavily glycosylated to help protect from lysosomal proteases

26

Delivery of lysosomal enzymes to lysosomes

- mannose-6-phosphate (M6P) tag added to lysosomal enzymes in ER/Golgi
- sorted into transport vesicles in trans Golgi for delivery to lysosomes via endosomes

27

3 lysosome delivery pathways

1. endocytosis: taken up into vesicles, delivered to early and late endosomes (ex. LDL)
2. phagocytosis: uptake by phagosomes, fuse with late endosomes/lysosomes. Occurs in macrophages and neutrophils ("pro phagocytes") ex. ingestion of bacteria by neutrophils
3. autophagy: digestion of pointless cell parts. Double mem surrounds organelle (forming autophagosome), fuses with late endosome/lysosome. ex. removal of expanded SER in liver

28

Mucopolysaccharidoses

- lysosomal storage disease
- defects in lysosomal enzyme required for degradation of glycosaminoglycans
- results in permanent progressive cell damage. Appear normal at birth, decline in mental/physical function over time

29

Oligosaccharidoses

- lysosomal storage disease
- defects in lysosomal enzymes required for degradation of oligosaccharides
- onset in infancy or early childhood, variable phenotype but facial dysmorphism and progressive mental retardation are common

30

Sphingolipidoses

- lysosomal storage disease
- defects in lysosomal enzymes required for degradation of sphingolipids

31

Inclusion-cell disease

- lysosomal storage disease
- defect in enzyme responsible for generating M6P tag on hydrolases
- hydrolases fail to target to lysosomes, so they are secreted from cell via default pathway
- hydrolytic enzymes missing from lysosome
- results in accumulation of many undigested substrates forming inclusion bodies
- onset in infancy with dev. delay and growth failure, progresses until death by age 5-8