Proteoglycans Flashcards
(58 cards)
1
Q
What is the basic function of proteoglycans?
A
allow connective tissues of the ECM to be able to withstand compressional forces through hydration and swelling.
2
Q
How many different proteoglycans are there?
A
30
3
Q
What is the function of proteoglycans?
A
Even though diverse in structure but functionally very similar.
- immobilize matrix proteins
- resevoir for proteins and protects them
- presents ligands to cell surface receptors
4
Q
What are common GAGs (glycosaminoglycans)?
A
- hyaluronic acid (not sulfated)
- dermatan and chondroitin sulfate
- heparan sulfate
- keratan sulfate
5
Q
What is the basic structure of proteoglycan?
A
- a polypeptide chain (proteo) with polysaccharide (glycan or GAG) side chains; >95% are carbohydrate.
- composed of copolymer of two different glucose-like units: an acidic sugar and amino sugar with negatively charged sulfate group.
6
Q
How are the proteoglycan’s sugar chains attached to the core protein?
A
covalent bonds
7
Q
How are proteoglycans so diverse?
A
- number of different core proteins
- different numbers of sugar chains
- various lengths of sugar chians
- various composition of sugar chains
8
Q
What links the GAGs to core protein?
A
tetrasaccharide or a trisaccharide linker
9
Q
Where can you find perfecan?
A
muscle
10
Q
where can you find aggrecan?
A
cartilage
11
Q
where can you find lumican?
A
bone
12
Q
where can you find syndecan and glypican?
A
cell surface; intergrated the cell membrane
13
Q
where can you find neuocan?
A
brain
14
Q
where can you find versican?
A
blood
15
Q
where can you find lumican?
A
cornea
16
Q
What is the structural property of GAGs?
A
- ## extends perpendicularly from the core protein in a brush like structure
17
Q
Where are the PGs and GAGs primarily found?
A
surface of cells or in the ECM
18
Q
What is one component that is always there?
A
amino sugar
19
Q
What makes up 50% of stiffness in articular cartilage?
A
electrostatic interactions between charged groups in GAG side chains of PG
20
Q
Where are proteoglycans modified post translationally?
A
ER, golgi, nucleus, extracellular compartment
21
Q
What is added to core protein group post translationally?
A
carbohydrate groups; heavily glycosylated, sulfated or carboxylated
22
Q
what is the benefit of proteoglycans modified post translationally?
A
proper folding of proteins
stability
cell to cell dhesion
23
Q
What would you find N-linked?
A
glucosamine attached to asparagine
24
Q
What would you find O-linked?
A
sugar attached to serine, threonine
25
What is the difference between glycoprotein & proteoglycan?
Glycoprotein: proteins conjugated saccharides lacking a repeat unit
Proteoglycan: proteins conjugated with serial repeat untis
26
what are the specialized properties of PG and GAGs?
❑ Negatively charged under physiological conditions (S03-, COO-).
❑ Strongly hydrophilic, can bind large amount of water.
❑ Gel like matrix: Hydrogel, highly shock absorbing
❑ The diverse structural properties of GAGs are important for molecular
interactions and for tissue morphogenesis.
❑ Extended conformation that imparts high viscosity to the solution. Along
with the high viscosity comes low compressibility (lubrication fluid in the
joints).
❑ Provides structural integrity to cells and provides space between cells,
allowing for cell migration, proliferation and differentiation.
❑ Important components of extracellular matrices (ECMs).
❑ Most abundant in those tissues where ECM is highly hydrated (high water
content).
❑ PGs have multiple functions that depend on their protein and carbohydrate
composition.
27
Chondroitin sulfate.
Where can you find it?
What are the common CS-PGs?
What happens to the loss of CS?
- In cartilage, bone, heart valves.
- CS-PGs: Aggrecan, Versican,
Brevican, Neurocan.
- Loss of CS from cartilage contributes
to osteoarthritis.
28
Dermatan sulfate.
Where can you find it?
What is the function?
- In skin, blood vessels, heart valves,
tendons, lung.
- Function in coagulation, wound repair,
fibrosis, and infection.
29
```
Keratan sulfate.
Where can you find it?
Where are KS chains synthesized?
What happens when the degree of sulfation alters KS?
What is different about this GAG?
```
- cornea, bone, cartilage
- Synthesized on 2 types of protein linkage:
1. oligiosaccharide O-linked to threonine
2. oligiosaccharide N-linked to asparagine
- macular degeneration
- galactose instead of acid sugar in disaccharide repeat unit
30
Heparan sulfate. What is the function? What are the major HS-PG forms?
Function: co-receptors for growth factors, chemokines facilitate cell adhesion to the ECM
- syndecans, glypicans
31
Hyaluronic acid.
Where can you find HA?
Why is HA unique? What is their special property?
- synovial fluid, articular cartilage, skin, and ECM pf loose CT
- unique because its not sulfaed and not covalently attached to core proteins as PG
- special: displace a large volume of water, an excellent lubricator and shock absorber
32
Where are sulfate groups added to sugar hydroxyls?
position 2,4,6
33
```
List the position of where sulfate is added to the following GAGs.
hyaluronic acid
chondroitin sulfate
dermatan sulfate
heparin sulfate
keratan sulfate
```
HA: only one not sulfated
CS: usually one sulfate on the 4 or 6 position of galactosamine
DS: sulfated primarily at the 4 position of galactosamine and atthe 2 position iduronic acid residues.
HS: sulfated primarily at the 6 position of glucosamine residues.
KS: sulfated primarily at the 6
position of N acetylglucosamine
and some of galactose residues.
34
What enzyme does sulfation?
sulfotransferase
35
What are the reasons for sulfation of GAGs?
- structural heterogenity
- strong negative charge which allows for binding of water, hydrodynamic strength
- allow for GAGs to bind to diverse signaling molecules (growth factors, cytokines, chemokines. morphogens)
- regulate the diffusion/sequestration/presentation of these signaling molecules in a highly specific manner
36
What is the major PG in cartilage?
aggrecan
37
What is the function of PGs in cartilage?
- controls biochemical and mechanical properties of cartilage
- expanding and hydrating the matrix of articular cartilage, higher load bearing function
- PGs embedded in collagen type 2,10 and elastin fibers
38
Aggrecasn complex.
Where is it most abundant?
What collagen is it mostly associted with?
- Highly abundant in cartilage and vertebral disc.
| - Associated with collagen type 2,9.10,11
39
Describe the 3D structure of aggrecan complex.
- The core protein has 3 globular domains: G1,2,3
- Contains mainly chondroitin sulfate, with age, CS is replaced with keratan sulfate
- G3 is CS rich
- G2 is KS rich
- PG is attached to HA by link protein
40
Why is the link protein in aggrecan complex important?
- ternary complex = G1 + link protein
- interaction locks aggrecan to HA
- stabilized the aggregate structure
- deletion of link protein in cartilage leads to severe skeletal malformations and lethality
41
What is the mahor PG in bone?
small leucine rich proteoglycans (SLRPS)
42
SLRPS re assocated with what type of collagen?
type 1 collagen fibrils
43
What are the 3 major SLRPs?
decorin
biglycan
lumican
44
What side chains do decorin, biglycan, and lumican contain?
Decorin and biglycan = CS or DS side chains
| Lumican = KS side chains
45
What is the function of SLRPs?
matrix organization, mineral deposition, and crystal growth
46
How are PGs involved with mineralization?
- organization and assembly of ECM prior to mineral deposition
- polyanionic nature may contribute to attracting and binding Ca++ ions
- SLRPs present in the bone, predentin, and dentin
- in predentin= irregular pattern
- in dentin= found in regular pattern
- Predentin and dentin have two PGs: decorin adn biglycan
47
Compare PGs of bone and cartilage.
Cartilage has 5-7% of PGs; major PG:aggrecan.
| Bone has 1% or less of PGs; major PG: SLRPs
48
What is the shortcut verson of synthesizing PGs?
1. Core protein made in ER
2. Linkage region synth in the ER and Golgi
3. GAG chain polymerization in golgi
49
Where are GAGs first attached and polymerized to core proteins?
golgi apparatus
50
What is the initial reaction of synthesize PGs?
xylosyltransferase
51
What enzyme is involved in formation of linkage region?
glycosyltransferase
52
What is the enzyme that elongates the GAG chain?
glycosyltransferase
53
Provide the sequence of events in PGs biosynthesis.
a) Synthesis of the core protein in ER:
1. Xylose added to the hydroxyl group of a serine/threonine
by xylosyltransferase.
2. Two or three galactose and one glucuronic acid molecules added to form
tetra or trisaccharide linker by galactosyltransferase I and
glucoronosyl transferase.
b. Chain elongation: sequential addition of alternative acidic and amino
sugars donated by a) galactosyltransferase I &
II; b) glucoronosyl transferase I & II; c) N-acetylgalactosaminyl transferase.
c. Chain termination: a) Sulfation (sulfotransferase); b) cleavage
d. Further modification in Golgi apparatus
e. Degradation: Phagocytosis and lysosomal degradation ( proteinase, lysosomal
hydrolase and glycosidase)
54
What are mucopolysaccharidoses?
mutation in gene encoding lysosomal hydrolase
- characterized by accumulation of GAGs in various tissues --> skeletal and extracellular matrix deformaties and mental retardation
55
What is chondrodystrophies?
| What is this disorder associated with?
- defect in the sulphnation of growing PG chain
- affect development and maintenance of skeletal system
- associated with atherosclerosis, arthrtitis, cancer metastasis
56
explain how chondrodystrophies are assoc with atherosclerosis
Dermatan sulphate
❑ Major CS & DS are major GAGs synthesized from arterial smooth muscle
❑ Binds to LDL
❑ Higher in smooth muscle cells during atherosclerosis
57
explain how chondrodystrophies are assoc with arthritis (osteoarthritis)
```
Chondroitin sulphate
▪ With age Chondroitin Sulphate
decreased
▪ Increased Keratan Sulphate and HA
▪ Increased activity of Aggrecanase
▪ Degrade Aggrecan
```
58
explain how chondrodystrophies are assoc with cancer
Hyaluronic acid
a. Tumor cell migration through ECM
b. Tumor cells induce fibroblasts to increase the synthesis of HA
Heparan Sulphate
a. Tumor cells secret less heparin sulphate
Resulting less adhesiveness
