Lecture 3- Extracellular Matrix I

Question 1

What is the ECM?

Answer 1

• A network of proteins and carbohydrates filling spaces between cells
• fibrillar and non-fibrillar components

Question 2

What is its function?

Answer 2

• Physical support
• Influences growth, adhesion and differentiations status of cells
• Needed for development- tissue function and organogenesis

Question 3

Describe the structure of metazoans and give an example of it

Answer 3

Hydra vulgaris

- 2 layers of epithelia with ECM in the middle

Question 4

What are the three components of connective tissues?

Answer 4

1) COLLAGENS
- Type I, II, III (fibrillar)
- Type IV (basement membrane)
2) MULTI-ADHESIVE GLYCOPROTEINS
- Fibronectin
- Fibrinogen
- Laminins (basement membranes)
3) PROTEOGLYCANS
- Aggrecan
- Versican
- Decorin
- Perlecan (basement membrane)

Question 5

Which molecules are found only in basement membranes?

Answer 5

1) Collagen- Type IV
2) Multi-adhesive glycoprotein- laminin
3) Proteoglycan- Perlecan

Question 6

Name 5 disorders caused by mutations affecting matrix proteins and the protein they affect

Answer 6

1) Osteogenesis imperfecta- Type I collagen
2) Marfan’s syndrome- Fibrillar 1
3) Alport’s syndrome- Type IV collagen (a5)
4) Epidermolysis Bullosa- Laminin 5 (all 3 chains)
5) Congenital Muscular Dystrophy- Laminin 2 (a2 chain)

Question 7

Name 2 disorders caused by mutations affecting ECM catabolism

Answer 7

1) Hurler’s syndrome- L-a-iduronidase

2) Other mucopolysaccharidoses- inability to degrade GAGs

Question 8

What can be caused by excessive ECM deposition and give the names of these disorders affecting the lungs, kidney and liver

Answer 8

Fibrosis

• Liver fibrosis= cirrhosis
• Kidney fibrosis= diabetic nephropathy
• Lung fibrosis= silicosis

Question 9

Give an example of a disorder caused by loss of ECM

Answer 9

osteoarthritis

Question 10

What are the properties of different connective tissues: tendons, bone, vitreous humour, cartilage. What do these properties depend on?

Answer 10

Tendons: tough + flexible
Bone: Hard and dense
Vitreous humour: soft + transparent
Cartilage: resilient + shock absorbing
- arrangement of collagen
- composition of ECM

Question 11

What is the relationship between ECM and connective tissue?

Answer 11

Connective tissue= ECM + component cells (macrophages etc.)

Question 12

What is the molecular structure of the different types of collagens?

Answer 12

• Type I collagen: [a1(I)]2[a2(I)] –> from 2 different genes
• Type II collagen: [a1(II)]3
• Type III collagen: [a1(III)]3
  ^^ have only one chain type

Question 13

What gives skin, bone and corneas tensile strength?

Answer 13

• Collagen fibrils laid down at right angles

- can resist force in two direction

Question 14

Which amino acids are collagens made up of?

Answer 14

Every third aa is glycine because to is the only one small enough to fit in the middle of the triple helix: Gly-x-y pattern

Question 15

How does a collagen fibre come together?

Answer 15

• sequence of 3 amino acids -> one alpha chain
• 3 alpha chains wrap around -> triple helix
• individual triple helices come together -> collagen fibrils
• collagen fibrils come together -> collagen fibres

Question 16

Explain the biosynthesis of fibrillar collagen, its post- translational modifications and how it is assembled into fibrillar structures

Answer 16

1) Synthesis of PRO-a chain
2) Hydroxylation of selected prolines and lysines
3) Glycosylation of selected hydroxylysines
4) Three a chains binds= procallagen in RER with N and C- terminal propeptides
5) Procollagen secreted from cells
6) Fibrillar collagen domains removed by peptidases
7) Collagen molecules associate laterally and staggered –> collagen fibrils
8) Covalent cross links between molecules form (tensile strength)
9) Parallel bundles of collagen fibrils –> fibres with high tensile strength

Question 17

Describe the functional significance of modifying lysine and proline within collagen

Answer 17

1) Lysine and Proline can be hydroxylated –> to form H bonds
- this is done by hydroxylases
2) Lysine an Hydroxylysine can be modified –> to form covalent cross linkages

Question 18

What happens when you have Vitamin C deficiency?

Answer 18

• The hydroxylates need Fe2+ and Vitamin C

- Deficiency –> underhydroxylated collagens –> poor tissue stability –> SCURVY

Question 19

What other types of collagen are there which aren’t fibrillar and what are their functions?

Answer 19

1) Type IX and XIII: Fibril-associated collagens, regulate the organisation of collagen fibres
2) Type IV: network forming collagen in basement membranes. Sheet- like networks

Question 20

What is the importance of elastic fibres?

Answer 20

• Elasticity of tissues

- found interwoven with collagen to limit extent of stretching

Question 21

What are elastic fibres made of?

Answer 21

Core of elastin

Surrounded by microfibrils rich in fibrillin

Question 22

Describe the structure of elastin

Answer 22

• Made of two types of alternating segments: hydrophobic regions, a-helical regions (rich in alanine and lysine)
• lysines are boss linked
• When stretched out, the molecules form lines but go curly when relaxed

Question 23

Describe some of the features of Marfan’s syndrome

Answer 23

• Mutation in genes coding for fibrillin-1

- Affects skeletal, ocular and CVS (higher risk of aortic ruptures)

Question 24

What are basement membranes?

Answer 24

• flexible, thin mats of ECM under epithelial layers

Question 25

Where can basement membranes be found

Answer 25

Kidney Glomerulus

Question 26

Describe the pathology of conditions associated with the basement membrane

Answer 26

1) Diabetic Nephropathy- excess ECM deposition in kidney –> pushes against capillaries–> restricts renal filtration
2) Alport’s syndrome - mutation in collagen IV –> abnormally laminated GBM