Fibrous extracellular matrix proteins
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What are examples of connective tissue?
• Blood • Bone • Tendon • Skin • Ligament
What pathological conditions are associated with abnormalities of the extracellular matrix?
• Arthritis • Osteoporosis • Cancer • Diabetes • Ageing • Scars/fibrosis
What are 2 important fibrous proteins that make up the extracellular matrix?
Collagen + elastin
How are the collagen fibrils arranged in: • tendons/ligaments • bone • cartilage
• tendons/lig - parallel bundles • bone - spirals • cartilage - meshwork
How many alpha chains are there in collagen forming the helix?
3 a chains - triple helix Triple helices cross-link to form a FIBRIL
Each a chain is typically 3 amino acid repeats, what are they?
Glycine - proline - hydoxyproline (Glycine ALWAYS as it acts as the glue, the other two are usual but not always)
Describe the pathway for synthesis of fibril-forming collagens
• Pro-alpha chains modified in ER • Triple helix formed -> procollagen • (extracellular) Procollagen secreted • Propeptides cleaved -> collagen • Striated + strength
How many known alpha chains are there for collagen structure?
25 known a-chains, >10,000 possibilities but only 20 types of collagen molecules found
What are the 3 most important collagen types?
I, II, III
Where is collagen type I found?
Bone
Where is collagen type III found?
Woven bone (not as strong as type I)
Where is collagen type II found?
Hyaline cartilage
What is the difference between a collagen fibril and fibre?
• Collagen molecule = 3 alpha chains forming a triple helix • Collagen fibril = lots of overlapping molecules • Collagen fibre = lots and lots of fibrils
Collagen types I and III are fibrillar collagens. There is another type called sheet-like collagens, how are they different + give an example?
• 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
What substances help to increase synthesis of extracellular matrix?
• TGF-beta (transforming growth factor-beta) • PDGF (platelet derived growth factor)
What decreases synthesis of extracellular matrix?
• Glucocorticoids • Age
What substances increase degradation of extracellular matrix?
MMPs (matrix metalloproteinases)
What substances decrease degradation of extracellular matrix?
TIMPs - tissue inhibitors of MMPS
What does collagenase (MMP1) destroy?
Native fibrillar collagens (type I, III etc)
What does gelatinase (MMP2/9) destroy?
• Denatured collagens • Elastin • Type IV (sheet like) collagen
What does stromelysin (MMP3) destroy?
• Type IV collagen • Fibronectin • Proteoglycans
Which proteolytic enzyme is involved in bone resorption?
Cathepsin K
What happens in scurvy?
• Loss of collagen • Loss of glycine -> forms sheet-like collagen instead • peridontal ligament (in teeth) broken down -> teeth fall out
There is a type 1 collagen mutation in osteogenesis imperfecta. What is glycine replaced with?
Cysteine -> disrupts alpha helix