extracellular matrix

Question 1

extracellular matrix

Answer 1

• provides a scaffold for tissue development
• provides a mechanical basis for cell attachment and movement
• transmits force (tendon, ligament, cartilage, bone)
• can withstand compression in cartilage and intervertebral disc
• provides survival signals to cells and differentiation signals to stem cells
• reservoir for growth factors
• The matrix is an integral component of multicellular life and tissues require it. In fact in during our lives the importance of the matrix to our body increases as in adults 80% of bodyweight is due to the ECM. So as you can see as we age our cells keep producing matrix.

Question 2

composition of ECM

Answer 2

Water (50%)
Proteins
Glycoproteins (protein with sugar molecules attached)
Proteoglycans (GAG side chain- bind water for withstanding compression forces)
Glucosaminoglycan (GAG)

Question 3

collagen biology

Answer 3

30% of protein mass

Major component of connective tissue

Gly-X-Y repeat
Proline, hydroxyproline

Triple helical structure

Tensile forces

Hydroxy proline is important for helix stability
Hydroxylusine is important for glycosylation

Question 4

collagen maturation

Answer 4

During collagen folding cis to trans coversion is required which is achieved by cic-transisomerase called cyclophilin B. This works on gly-pro but not hydroxyproline. This isomerisation slows down triple helix formation and that allows times for glycosylaton and hydroxylation

Galactosyl and glycosyl transferase react with hydroxylysine
Hydroxyproline : hydroxy group means ring/pucker of sticks upwards away from triple helix

Question 5

collagen disease

Answer 5

• most often mutations affect glycine
  -dominant and recessive disease
• original hypothesis- structural defects

Question 6

osteogenesis imperfecta

Answer 6

Brittle bone disease
Range of clinical severity from fractures to lethality
Autosomal recessive and dominant forms
Collagen type I related disorder
Major fibrillar collagen
COL1A1 and COL1A2 heterotrimeric protomer

Question 7

osteogenesis imperfecta type 1

Answer 7

Less severe, no-symptomatic at birth
Early onset osteoporosis, few fractures
Null mutations- lead to non-functional protein

Reduced collagen levels

Question 8

mutation in OI

Answer 8

• stop codons
• promoter mutations
  -mRNA instability
• mutation in SERPINH1 (HSP47)- leads to delayed collagen secretion from cells

Question 9

severe forms forms of OI

Answer 9

80% glycine missense mutations
Dominant negative

Effect on modification due to delay in folding

Secretion of mutant chains

Potential effects on protein binding

Question 10

severe OI mutation

Answer 10

• disruption of the gly-X-Y sequence slows the rate of folding resulting in overmodificaton of the chains N-terminal to the disruption.