Extracellular matrix Flashcards
What is the ECM and what is it made up of
The extracellular matrix is the connective tissue that makes up the space between cells and consists of carbohydrates and proteins with fibrillar and non-fibrillar components
What role does ECM play in tissues
The extracellular matrix provides physical support to cells in a tissue, determines the physical and chemical properties of a tissue, it influences cell growth, differentiation and adhesion, it is required for development and organogenesis
What does connective tissue consist of
Connective tissue consists of collagen, fibroblasts secreting ECM such as glycosaminoglycans, often also contain capillaries and mast cells
Which cells synthesise substances of ECM
Fibroblasts synthesise the substances of the ECM, such as collagen, glycosaminoglycans, proteoglycans and glycoproteins
What are the three major molecular components of connective tissues
Collagens, multi-adhesive glycoproteins and proteoglycans are the main molecular components of connective tissues and the ECM
What is the basement membrane
The basement membrane is a layer of extracellular matrix that is found under epithelial layer and divides the epithelium and the connective tissue or other tissues =
What are the major components of basal lamina
Collagen type IV, laminins and perlecan
Where are basement membranes found in human body
Basement membranes surround muscles, peripheral nerve and adipose tissues and underlie most epithelia
What is basement tissue for filtration in kidney called
Glomerular basement membrane (GBM)
What happens to the glomerular basement membrane in diabetic nephropathy
In diabetic nephropathy, there is an accumulation of extracellular matrix in the glomerular basement membrane which leads to thickening that inhibits renal filtration and leads to renal failure
What happens to the glomerular basement membrane in Alpert syndrome and what are other symptoms
In Alpert syndrome there is a genetic mutation in type IV collagen, which leads to abnormal glomerular basement membrane and progressive loss of kidney function and also hearing loss
What are elastic fibres made up of and where are they found in body
Elastic fibres are made up of a core of elastin and microfibrils surrounding it made up of fibrillin
What is the function of fibrillin
Fibrillin forms microfibrils that maintain the integrity of the elastic fibres
What is Marfan’s syndrome and what are its manifestations
In Marfan’s syndrome there is a mutation in fibrillin which leads to loss of elastic fibre integrity and manifests in skeletal system as arachnodactyly and cardiovascular system with high risk of aortic rupture and ocular problems
What is elastin protein made up of and how can it stretch
The elastin protein is made up of two segments; alternating hydrophobic regions and a-helices containing lysine and alanine. The crosslinked elastin proteins are coiled and when the elastic fibre is stretch, they uncoil and form straight protein chains
How are elastin proteins crosslinked in elastic fibre
The lysine residues in a-helix regions of the elastin crosslinks with other elastin polypeptides to form a network
Where are collagens found and how much of collagen in mammals
Collagens are found in bone, tendon, skin, connective tissue and 25% of protein mass of mammals consists of collagen
How does collagen arrangement resist tensile force
When collagen fibres are directed in different directions, it can resist force in all different directions
Which tissues contain layers of perpendicular collagen
The skin, mature bone, cornea, all tissues that must resist tensile force contain perpendicular successive layers of collagen
How many chains does collages consist of and what is the characteristic repetition
Collagen consists of three alpha chains that form a triple helix, and the chains have a repetion of glycine-x-y where x often is proline and y hydroxyproline
What classifies different collagen types
The different combination of alpha chains in the triple helix defines which type a collagen is
In characteristic repetition in collagens, what is x and y often
The characteristic repetition in collagen often consists of glycine then proline as x and hydroxyproline as y
Why does characteristic repeat contain glycine
Glycine is an amino acid with a small residue that can point inwards and hold the chains in the helix together
How long are alpha chains in fibrillar collagens approximately
Alpha chains in fibrillar collagens consist of approximately 1000 amino acids
How is triple chain collagen molecule organised in connective tissue
The collagen helixes form bundles called collagen fibrils that form bundles called collagen fibres
What is difference between collagen inside and outside of cell
Newly synthesised collagen chains contain non-collagenous N- and C-domains in intracellular collagen that have to be cleaved from the protein to form the extracellular collagen
How can extracellular collagen be synthesised from procollagen
The non-collagenous N- and C-domains have to be removed when procollagen is transport out of the cell to form collagen
How is the tensile strength and stability of the fibril increased
By cross-linking the collagen triple helixes, the tensile strength and stability of the collagen fibril and fibre are increased
What amino acid residues are involved in cross-linking of the collagen
Lysine and post-translationally modified hydroxylysine are involved in cross-linking between collagen triplets
How does type and extent of crosslinking relate to tissue function and age
The amount of cross-linking relates to the forces the tissue must endure and with ages these cross-links tend to decrease in numbers and become less regularly patterned
What are the 9 steps of biosynthesis of fibrillar collagen
- The synthesis of pro-a-chains, 2. the hydroxylation of selected lysine and proline residues, 3. the glycosylation of a-chains, 4. the self-assembly of the pro-a-chains, 5. triple helix formation of three pro-a-chains, 6. secretion of procollagen, 7. the cleavage of non-collagenous N- and C-domains, 8. self-assembly into fibrils and crosslinking, 9. aggregation of fibrils into fibres
What residues are needed for formation of cross-links and what does this require
Lysine and hydroxylysine residues in the collagen proteins are required for cross-linking, this requires lysyl oxidases which crosslinks hydroxylysine and lysine together
What can a vitamin-C deficiency result in relating to collagen
Vitamin-C deficiency can lead to inhibition of hydroxylation of collagen and this underhydroxylation can lead to loss of collagen stability and tissue stability and this is scurvy
What are Ehlers-Danlos syndromes and what is their cause
Ehler-Danlos syndromes are a group of genetic disorders that cause stretchy skin and loose joints, caused by mutations in collagen that affect collagen production, structure or processing
What do collagen types IX to XII do and what is this type of collagen called
Collagen type IX to XII are called fibril-associated collagen and associate with collagen fibrils to regulate their organisation
What is type IV collagen, where is it found and what is this type of collagen called
Type IV collagen is a network-forming collagen, found in all basement membranes but constitution can vary from tissue to tissue
How does type IV collagen form networks and what is different in secondary structure to fibrillar collagens
In type IV collagen, the uncleaved N- and C-terminals interact to connect monomer chains to form a network in a mesh-like structure. In fibrillar collagens, the N- and C-terminals are cleaved.
What is the function of the hydroxylation of lysine and proline residues in collagen fibrils
The hydroxylysine and hydroxyproline can form hydrogen bonds between collagen triplets and this can increase the strength of the collagen fibrils and fibres
What do the modular protein domains in extracellular matrix proteins do
The modular domains can make it possible for a protein to bind to many different structures in the extracellular matrix and cell-surface receptors
What do laminins consist of and what shape do they adopt
Laminins are heteromeric proteins consisting of an alpha-, beta- and gamma-chain that adopts a form of a cross
What can multi-adhesive laminins bind to in basement membrane and other ECM
Multi-adhesive laminins can self-associate in the basement membrane, but can also bind to integrins, collagen type IV and nidogen and to cell-surface receptors like integrins and dystrogen
What is congenital muscular dystrophy caused by and what are its symptoms
In congenital muscular dystrophy there are mutations in the alpha-chain of laminin and this causes symptoms like hypotonia, general weakness and deformities of joints
What regions does fibronectin consist of and how is the dimer connected
Fibronectin consists of a two large modular protein with collagen, integrin and heparin binding domains which are connected by disulphide bonds
Where can fibrinectins be found and in what two forms do they exist
Fibronectins can be found in extracellular matrix or in body fluids, either as insoluble fibrillar matrix or as soluble plasma protein
How are different fibronectin types formed
All fibronectins are formed from one encoding gene, which can be spliced differently to produce different forms of fibronectin
In what processes play fibronectin important roles
In cell adhesion and migration, particularly in embryogenesis and wound repair, and in blood clotting
How do fibronectin and actin form a mechanical continuum and what is its function
Fibronectin is bound to integrins which are bound to actin and hence it forms an attachment point for the cell to the extracellular matrix at the sites where it is enforced by the actin cytoskeleton
What do proteoglycans consist of
Proteoglycans consist of a core protein which one or many more glycosaminoglycans (GAGs) attached
What do GAGs consist of and why do they often carry charge
Glycosaminoglycan chains consist of disaccharide repetitive units of which one or two are amino sugars. They often carry negative charge because they often contain sulfate or carboxyl groups
What are the four principal proteoglycan families
Basement membrane proteoglycans, aggregating proteoglycans (that bind to hyaluronan), small leucine-rich proteoglycans, cell surface proteoglycans
What are the four major GAG chains in human tissue
Hyaluronan, chondroiton sulfate and dermatan sulfate, heparan sulfate, keratan sulfate
Where are GAGs synthesised and attached to core protein and what is the exception
GAGs and the core proteins are synthesised in the fibroblasts in the connective tissues, but hyaluronan is directly formed by an enzyme on the cell surface
What kind of proteoglycan is perlecan
Perlecan is a basement membrane proteoglycan
How many GAGs can proteoglycan possess
Proteoglycans can carry up to 100 GAGs per core protein
What does hyaluronan consist of and where is it found
Hyaluronan is a long carbohydrate chain consisting of glucoronic acid and N-acetylglucosamine, which is found in the extracellular matrix of soft connective tissue
Where is hyaluronan used for high viscosity
Hyaluronan is found in the vitreous humour of the eye and the synovial fluid of joints, where it protects the cartilage surface from damage
What is special about hyaluronan polymerisation
It can reach enormous sizes of more than 10.000 disaccharides polymerised
What does cartilage tissue consist of and how can it resist compressive force
The extracellular matrix in cartilage tissue is produced by chondroctyes and consists mainly of aggrecan, a highly sulfated and carboxylated proteoglycan that contracts cations such as sodium because it is so negatively charged. This makes it osmotically active and retain a lot of water. Under compressive force, this water is pressed out of the extracellular matrix and reabsorbed when the force is relieved. It also contains collagen and elastin.
What does aggrecan consist of
Aggrecan consists of a core protein with a hyaluronan binding region and the GAGs chondroitin sulfate and keratan sulfate attached containing high negative charge
What is osteoarthritis and what is the problem in function of cartilage
Over time, aggrecan in the cartilage is cleaved by aggrecanases and metalloproteinases that result in loss of aggrecan that can resist compressive force, which leads to damage of the cartilage layer and the bone layer below
What causes fibrotic diseases
The excessive production of extracellular matrix in fibrous connective tissue, often after infection, causes fibrotic diseases
