Fibrous extracellular matrix proteins

Question 1

What are examples of connective tissue?

Answer 1

• Blood
• Bone
• Tendon
• Skin
• Ligament

Question 2

What pathological conditions are associated with abnormalities of the extracellular matrix?

Answer 2

• Arthritis
• Osteoporosis
• Cancer
• Diabetes
• Ageing
• Scars/fibrosis

Question 3

What are 2 important fibrous proteins that make up the extracellular matrix?

Answer 3

Collagen + elastin

Question 4

How are the collagen fibrils arranged in:

• tendons/ligaments
• bone
• cartilage

Answer 4

• tendons/lig - parallel bundles
• bone - spirals
• cartilage - meshwork

Question 5

How many alpha chains are there in collagen forming the helix?

Answer 5

3 a chains - triple helix

Triple helices cross-link to form a FIBRIL

Question 6

Each a chain is typically 3 amino acid repeats, what are they?

Answer 6

Glycine - proline - hydoxyproline

(Glycine ALWAYS as it acts as the glue, the other two are usual but not always)

Question 7

Describe the pathway for synthesis of fibril-forming collagens

Answer 7

• Pro-alpha chains modified in ER
• Triple helix formed -> procollagen
• (extracellular) Procollagen secreted
• Propeptides cleaved -> collagen
• Striated + strength

Question 8

How many known alpha chains are there for collagen structure?

Answer 8

25 known a-chains, >10,000 possibilities but only 20 types of collagen molecules found

Question 9

What are the 3 most important collagen types?

Answer 9

I, II, III

Question 10

Where is collagen type I found?

Answer 10

Bone

Question 11

Where is collagen type III found?

Answer 11

Woven bone (not as strong as type I)

Question 12

Where is collagen type II found?

Answer 12

Hyaline cartilage

Question 13

What is the difference between a collagen fibril and fibre?

Answer 13

• Collagen molecule = 3 alpha chains forming a triple helix
• Collagen fibril = lots of overlapping molecules
• Collagen fibre = lots and lots of fibrils

Question 14

Collagen types I and III are fibrillar collagens. There is another type called sheet-like collagens, how are they different + give an example?

Answer 14

• Type IV - in skin
• Lack regular glycine -> loose helix -> inc flexibility
• -> Sensitivity to digestion with proteases (so easily destroyed)
• Terminal peptides not cleaved
• Assemble head-to-head, form a sheet

Question 15

What substances help to increase synthesis of extracellular matrix?

Answer 15

• TGF-beta (transforming growth factor-beta)
• PDGF (platelet derived growth factor)

Question 16

What decreases synthesis of extracellular matrix?

Answer 16

• Glucocorticoids
• Age

Question 17

What substances increase degradation of extracellular matrix?

Answer 17

MMPs (matrix metalloproteinases)

Question 18

What substances decrease degradation of extracellular matrix?

Answer 18

TIMPs - tissue inhibitors of MMPS

Question 19

What does collagenase (MMP1) destroy?

Answer 19

Native fibrillar collagens (type I, III etc)

Question 20

What does gelatinase (MMP2/9) destroy?

Answer 20

• Denatured collagens
• Elastin
• Type IV (sheet like) collagen

Question 21

What does stromelysin (MMP3) destroy?

Answer 21

• Type IV collagen
• Fibronectin
• Proteoglycans

Question 22

Which proteolytic enzyme is involved in bone resorption?

Answer 22

Cathepsin K

Question 23

What happens in scurvy?

Answer 23

• Loss of collagen
• Loss of glycine -> forms sheet-like collagen instead
• peridontal ligament (in teeth) broken down -> teeth fall out

Question 24

There is a type 1 collagen mutation in osteogenesis imperfecta. What is glycine replaced with?

Answer 24

Cysteine -> disrupts alpha helix

Question 25

What happens in achondrogenesis?

Answer 25

Type II collagen mutation - severe effects on development of cartilage and bone

Question 26

What happens in Ehlers-danlos syndromes?

Answer 26

Type III or V collagent mutation - joint hyper mobility, skin extensibility, rupture of blood vessels

Question 27

Elastin core is covered by sheath of microfibrils. The microfibrils are composed of which glycoprotein namely?

Answer 27

Fibrillin The microfibrils are essential for integrity of elastic fibres

Question 28

Does elastase increase or decrease synthesis of elastin? What inhibits elastase?

Answer 28

Decrease - it is inhibited by a1-anti-trypsin

Question 29

What happens to elastin synthesis in hypertension?

Answer 29

Increased synthesis and deposition of elastin and collagen in vessel walls - they become thickened and diameter becomes reduced. The turnover of elastin + collagen is slow, so difficult to treat.

Question 30

What happens to elastin in pulmonary emphysema?

Answer 30

Loss of elastin = reduced elasticity of the lungs, sometimes due to deficiency of a1-anti-trypsin - needed to inhibit elastase. So too much elastase = excessive degradation.

Question 31

What is cutis laxa?

Answer 31

Loss of elastin - makes skin appear wrinkly

Question 32

What is Marfan syndrome?

Answer 32

Mutation in fibrillin gene -\> arachnodactyly, pectus excavatum, dilation of aorta