4. Extracellular Matrix II

Question 1

List the 3 major components of the ECM

Answer 1

Collagens
Glycoproteins
Proteoglycans

Question 2

What do ECM molecules consist of?

Answer 2

Large, modular proteins
50-200 AAs
Multifunctional and multi-adhesive

Question 3

Give 2 examples of multi-adhesive glycoproteins.

Answer 3

Fibronectin

Laminin

Question 4

Describe the structure of Laminin.

Answer 4

Cross shaped molecule consisting of an alpha, beta and gamma chain
Very large (160-400 kDa)
The N terminus of all the chains there are globular regions
There is a coiled-coil region in which the 3 chains are wrapped around each other

Question 5

What can laminin interact with?

Answer 5

Can self-associate as part of the BM
Can interact with:
Cell surface receptors e.g. integrins 
Type IV collagen
Proteoglycans

Question 6

What causes congenital muscular dystrophy?

Answer 6

Absence of alpha 2 chain in laminin 2

Question 7

Characteristics of congenital muscular dystrophy

Answer 7

Symptoms evident from birth
Hypotonia (abnormally decreased muscle tension)
Generalised weakness
Deformities of the joints

Question 8

Describe the structure of fibronectins

Answer 8

Large multi-domain molecule: dimer (500 kDa) joined by disulphide bonds
Insoluble fibrillar matrix or soluble plasma protein
Derived from 1 gene (alternate splicing at mRNA level)

Question 9

What do fibronectins interact with?

Answer 9

Cell surface receptors and other matrix molecules

Question 10

What important roles are fibronectins involved in?

Answer 10

Regulating cell adhesion and migration in embryogenesis and tissue repair
Wound healing

Question 11

What do fibronectins form a mechanical continuum with and how?

Answer 11

Actin cytoskeleton of many cell types

Integrin receptors

Question 12

Why is fibronectin considered essential for life?

Answer 12

There are no known mutations of fibronectin in humans

Question 13

What part of fibronectin do integrins bind to?

Answer 13

RGD motif

Question 14

Describe the general structure of proteoglycans.

Answer 14

Consists of a core protein with 1 or more glycosaminoglycan (GAG) chains covalently attached

Question 15

What are glycosaminoglycans?

Answer 15

Long, unbranched sugars consisting of repeating disaccharides
Occupy huge volume relative to their mass

Question 16

What is a characteristic feature of GAG chains?

Answer 16

Can form hydrated gels which are resistant to compression

Question 17

Name 4 proteoglycan families

Answer 17

BM: e.g. perlecan
Aggregating: e.g. Aggrecan
Small leucine-rich: e.g. decorin
Cell surface: e.g. syndecans 1-4

Question 18

Variability in size of proteoglycans

Answer 18

Small: Have single GAG attached
Large: Carry 100 GAG chains

Question 19

What are the 4 families of GAG chains?

Answer 19

Hyaluronan
Heparan Sulfate
Chondroitin Sulfate and Dermatan sulphate
Keratan sulfate

Question 20

What is unique about hyaluronan structure?

Answer 20

Doesn’t have a core protein (simply carbohydrate chain)
Synthesised at the cell surface rather than by the ER
Un-sulphated
Single long chain up to 25,000 repeating disaccharides

Question 21

How are GAG chains linked to the core protein?

Answer 21

Connected via a link tetrasaccharide

Question 22

What is Decorin?

Answer 22

Small proteoglycan

Question 23

What does Decorin do?

Answer 23

Binds to collagen fibres, essential for fibre formation

Question 24

What is the most abundant type of cartilage?

Answer 24

Hyaline

Question 25

What does hyaline cartilage consist of?

Answer 25

Aggrecan aggregates

Aggrecan (GAG chains = keratan sulphate and chondroitin sulphate) associated with hyaluronan and a link protein

Question 26

Where is hyaline found?

Answer 26

nose
larynx
trachea
bronchi
ventral ends of ribs
articular ends of long bones

Question 27

What is the function of hyaline?

Answer 27

Cushion ends of long bones

Question 28

Describe how hyaline cartilage resists compressive force.

Answer 28

GAG chains in aggrecan are heavily sulphated and carboxylated so it is very negatively charged.
This means it can attract osmotically active cations (Na+ and Ca2+), which attracts water forming a gel like substance
Under compressive load, water is squeezed out and returns when the compressive force is removed
Therefore good for resisting compressive forces

Question 29

What causes osteoarthritis?

Answer 29

Loss of extracellular matrix

Over time aggrecan is cleaved and fragments are lost to synovial fluid

Question 30

What is the result of excess ECM degradation in osteoarthritis?

Answer 30

Cushioning properties of cartilage over ends of bones are lost

Question 31

What happens in fibrotic disorders?

Answer 31

Excess production and deposition of fibrous connective tissue