ECM Flashcards
- What is the ECM?
Complex network of proteins and carbohydrates
Comprises of fibrillar and non-fibrillar components
- What does fibrillar mean?
Fibre-making
- What are the key functions of the ECM?
Provides physical support
Determines mechanical and physiochemical properties of tissue Influences growth, adhesion and differentiation status of cells and tissues with which it interacts Essential for development, organogenesis and tissue function
- Where is the ECM?
- What is the ECM made of?
Spaces between cells
Collagens - e.g Type I, II, III (fibrillar) and Type IV (basement membrane) Multi-adhesive glycoproteins Proteoglycans
- What properties do connective tissues in the tendon and skin have?
- What properties do connective tissues in the bone have?
- What properties do connective tissues in the cartilage have?
Tough and Flexible
Hard and Dense Resilient and Shock-absorbing
- Give an example of a fibrotic disorder due to excessive ECM deposition
- Give an example of a disorder due to excessive loss of ECM
Liver Fibrosis - cirrhosis
Kidney fibrosis - diabetic nephropathy
Lung fibrosis - idiopathic pulmonary fibrosis (IPF)
Osteoarthritis
cushioning properties of cartilage over the ends of bones are lost
aggrecan is cleaved by metalloproteinases and aggrecanases
loss of aggrecan fragments to synovial fluid
- How is collagen arranged in skin, mature bone and cornea and how does this relate to its function?
Successive layers nearly at right angles to one another
This resists tensile force in all directions
- Describe the structure of collagen
- What is the difference between a heterotrimer and a homotrimer?
3 alpha chains
Forming a triple helix
Heterotrimer is collagen with more than one type of alpha chain Homotrimer is collagen with 3 of the same alpha chains
- Describe the structure of an alpha chain
gly-x-y repeat
Glycine X is often Proline Y is often hydroxyproline Each alpha chain is around 1000 amino acids long forming a left-handed helix
- Explain the biosynthesis of fibrillar collagen
- Occurs in Fibroblast
- Synthesis of pro-alpha chain
- Post-translational modifications - Hydroxylation of prolines and lysines and glycosylation of hydroxylysines
- Self-assembly of 3 pro-alpha chains
- Procollagen triple helix formation
- Secretion
- Cleavage of propeptides
- Self assembly into fibrils
- Aggregations of collagen fibrils to form a collagen fiber
- Which compounds are involved in the cross-linking of collagen?
- How are hydrogen bonds formed between collagen molecules?
Lysine
Hydroxy-lysine
Prolyl and Lysyl Hydroxylases use Fe2+ and Vitamin C as co-factors to form hydroxylysine and hydroxyproline Allowing them to form hydrogen bonds with one another
- What happens therefore, if there is a Vitamin C deficiency And what is this condition called?
Underhydroxylated collagens, so there are dramatic consequences for tissue stability
Scurvy
- What is Ehlers-Danlos Syndrome (EDS)
Group of inherited connective tissue disorders whose symptoms include fragile (stretchy) skin, blood vessels and loose joints
Negatively affecting collagen production, structure and processing
- What property does Collagen type IV have that promotes its function?
Uncleaved N and C termini allow it to interact with other Collagen molecules to form a network of collagen
Allows it to act as a basement membrane
- What is basement membrane (BM)?
- Where is BM found?
- what mutation is Alports syndrome associated with
Flexible, thin mats of extracellular matrix underlying epithelial sheets and tubes
Highly specialised ECM containing a distinct combination of collagen, glycoproteins and proteoglycans
Surround muscle, peripheral nerve and fat cells
Underlie most epithelia
mutation in type 4 collagen (alpha 5 chain)
- What are Diabetic Nephropathy?
- What is Alport Syndrome?
Highly thickened BM which restricts renal filtration leading to renal failure
Mutations in Collagen IV result in abnormally split and laminated GBM, associated with progressive kidney function loss and hearing loss
- What are elastic fibres made of?
- What condition are mutations in the protein fibrillin-1 associated with?
Core of protein elastin
Microfibrils - rich in the protein fibrillin
Marfan's syndrome - Spider-like fingers, tall and thin, long legs, arms, fingers, toes. overly flexible joints and scoliosis
- What is elastin composed of?
2 types of segment that alternate along polypeptide chain:
Hydrophobic region Alpha-helical regions rich in alanine and lysine (lysine chains are covalently cross linked)
- Describe the structure of Laminins?
- What makes Laminins multi-adhesive properties?
They are heterotrimeric proteins made up of an alpha-chain, beta chain and a gamma-chain
Forming cross chained molecules
They are multi adhesive proteins that can interact with a variety of cell surface receptors including integrins and dystroglycan
- What group of tissues tend to be affected by mutations of genes coding for Laminins?
- What causes congenital muscular dystrophy and what are the symptoms?
- what causes epidermolysis bullosa
Muscular
Alpha-2 chain in Laminin2 Hypotonia (abnormally decreased muscle tension), generalised weakness and deformities of the joints
mutation in all three chains of laminin 5
- What 2 forms can fibronectins exist as?
- Explain the multi-domain structure of fibronectin
Insoluble fibrillar matrix
Soluble plasma matrix
Several domains are linked by disulphide bonds Fibronectin then has several collagen binding sites and cell binding sites
- How is fibronectin involved in the binding of collagen fiber to actin filament?
Fibronectin binds to collagen fiber and the integrin receptor on the other side which provides linkage between matrix and cytoskeleton
Adaptor protein binds to other end of integrin Actin filament binds to adaptor protein
- What are proteoglycans?
Core proteins covalently attached to one or more glycosaminoglycan (GAG) chains
- What are the 4 proteoglycan families grouped upon their structural and functional characteristics
Basement membrane proteoglycans: e.g. perlecan
Aggregating proteoglycans (interact with hyaluronan): e.g. aggrecan Small leucine-rich proteoglycans: e.g. decorin Cell-surface proteoglycans: e.g. syndecans 1-4
- What are the functions of fibronectin?
Regulating cell adhesion and Migration in a variety of processes e.g. - embryogenesis and Tissue repair
Important in wound healing to promote blood clotting
- What are GAGs made of and what charge are they usually?
Repeating disaccharide units with one or two of these sugars being an amino sugar
Negative as they are sulfated or carboxylated
- What are the 4 main groups of GAGs according to the disaccharide repeating unit?
Hyaluronan
Chondroitin sulfate and dermatan sulfate Heparan Sulfate Keratan Sulfate
- What makes hyaluronan distinct from other GAGs?
- Where is hyaluronan found in high viscousity?
Simply a carbohydrate chain without a core protein
Vitreous humour of the eye In synovial fluids of joints
- Why do hyaluronan chains tend to occupy a relatively large volume?
Hyaluronan can undergo a very high degree of polymerisation
- How does Aggrecan’s presence lead to large quantities of water being retained by the environment it is in?
GAGs are highly sulfated, increasing negative charge
Also present are large numbers of negatively charged carboxyl groups Multiple negative charges attract osmotically active Na+ ions
- How is aggrecan perfectly suited to resist compressive forces in cartilage matrix?
Under compressive load, water is given up but is regained once the load is reduced
Suited to resist compressive forces
what are the functions of elastin and collagen and how do they work together
elastin- important for elasticity of tissues eg skin, blood vessels and lungs
collagen is important for tensile strength of tissues
they are woven together to limit the extent of stretching
what do fibril associated collagens do and give examples
associate with fibrillar components
regulate organisation of collagen fibrils
types 9 and 12
