Lecture 3- Extracellular Matrix I Flashcards
What is the ECM?
- A network of proteins and carbohydrates filling spaces between cells
- fibrillar and non-fibrillar components
What is its function?
- Physical support
- Influences growth, adhesion and differentiations status of cells
- Needed for development- tissue function and organogenesis
Describe the structure of metazoans and give an example of it
Hydra vulgaris
- 2 layers of epithelia with ECM in the middle
What are the three components of connective tissues?
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)
Which molecules are found only in basement membranes?
1) Collagen- Type IV
2) Multi-adhesive glycoprotein- laminin
3) Proteoglycan- Perlecan
Name 5 disorders caused by mutations affecting matrix proteins and the protein they affect
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)
Name 2 disorders caused by mutations affecting ECM catabolism
1) Hurler’s syndrome- L-a-iduronidase
2) Other mucopolysaccharidoses- inability to degrade GAGs
What can be caused by excessive ECM deposition and give the names of these disorders affecting the lungs, kidney and liver
Fibrosis
- Liver fibrosis= cirrhosis
- Kidney fibrosis= diabetic nephropathy
- Lung fibrosis= silicosis
Give an example of a disorder caused by loss of ECM
osteoarthritis
What are the properties of different connective tissues: tendons, bone, vitreous humour, cartilage. What do these properties depend on?
Tendons: tough + flexible Bone: Hard and dense Vitreous humour: soft + transparent Cartilage: resilient + shock absorbing - arrangement of collagen - composition of ECM
What is the relationship between ECM and connective tissue?
Connective tissue= ECM + component cells (macrophages etc.)
What is the molecular structure of the different types of collagens?
- 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
What gives skin, bone and corneas tensile strength?
- Collagen fibrils laid down at right angles
- can resist force in two direction
Which amino acids are collagens made up of?
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
How does a collagen fibre come together?
- 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
Explain the biosynthesis of fibrillar collagen, its post- translational modifications and how it is assembled into fibrillar structures
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
Describe the functional significance of modifying lysine and proline within collagen
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
What happens when you have Vitamin C deficiency?
- The hydroxylates need Fe2+ and Vitamin C
- Deficiency –> underhydroxylated collagens –> poor tissue stability –> SCURVY
What other types of collagen are there which aren’t fibrillar and what are their functions?
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
What is the importance of elastic fibres?
- Elasticity of tissues
- found interwoven with collagen to limit extent of stretching
What are elastic fibres made of?
Core of elastin
Surrounded by microfibrils rich in fibrillin
Describe the structure of elastin
- 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
Describe some of the features of Marfan’s syndrome
- Mutation in genes coding for fibrillin-1
- Affects skeletal, ocular and CVS (higher risk of aortic ruptures)
What are basement membranes?
- flexible, thin mats of ECM under epithelial layers
Where can basement membranes be found
Kidney Glomerulus
Describe the pathology of conditions associated with the basement membrane
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
