2.10 ECM Flashcards
What is the extra cellular matrix?
A complex network of proteins and carbohydrates that fill the spaces between cells
What type of components does the ECM consist of?
Fibrillar and non-fibrillar components
What does fibrillar mean?
Makes fibre
What are the two types of roles that the ECM plays in the cell?
An architectural role (influencing mechanical stability) and an instructional role (influences cell behaviour)
What three things is the ECM essential for?
Development, tissue function and organogenesis
What are three key functions of the ECM?
- Physical support
- Determines mechanical and physicochemical properties of tissue
- Influences the growth, adhesion and differentiation status of the cells and tissues
What type of tissue is particularly rich in extra cellular matrix?
Connective tissue
What are the three main components of the extra cellular matrix?
Collagens
Multi-adhesive glycoproteins
Proteoglycans
What is found in the basement membrane?
Type IV collagen (non-fibrillar)
Laminins
Perlecan
How can connective tissues have such varied properties?
The different types and arrangements of collagen, with the presence of different ECM components
What properties do connective tissues in tendon and skin have?
Tough and flexible
What properties do connective tissues in bone have?
Hard and dense
What properties do connective tissues in the cartilage have?
Resilient and shock absorbing
What cell produces collagen?
Fibroblasts
What is connective tissue made up of?
Extracellular matrix and component cells
What are 5 proteoglycans? (PADS V)
Perlecan
Aggrecan
Decorin
Syndecans 1-4
Versican
What type of protein is collagen?
Fibrous
How many different collagen types exist in humans?
28
What structure does collagen form?
Triple helix
What is meant by a homotrimer?
When there is only one chain type
Which types of collagen are homotrimers?
Type II and III
What are the compositions of type II and type III collagen?
Both have 1 chain type
What is meant by a heterotrimer?
When the chains arise from 2 genes
What type of collagen is a heterotrimer?
Type I Collagen
What is the composition of type I collagen?
What are commonly the amino acids x and y in the glycine-x-y-repeat?
X = proline
Y = hydroxyproline
Which amino acid occupies every third position in collagen proteins?
Glycine
Why is glycine heavily involved in the structure of collagen?
Glycine is the only amino acid which is small enough to occupy the interior of the triple helix
This gives collagen a stiff triple helix structure
What provides tensile strength and stability in collagen?
Intermolecular and intramolecular cross links
When does cross linking in collagen take place?
Only after the collagen has been secreted
What is an essential post-translational modification which contributes to interchain hydrogen bond formation?
The hydroxylation of proline and lysine
What enzymes are needed for the hydroxylation of proline and lysine?
Prolyl hydroxylase and lysyl hydroxylase
What do Prolyl hydroxylase and Lysyl hydroxylase requires as a co-factor?
Fe2+ and vitamin C
What happens to collagen when you have vitamin C deficiency? What is this called?
The collagen is underhydroxylated thus affecting tissue stability
This is called scurvy
When does the cross linking of collagen occur?
After the fibril formation
What are the steps to collagen synthesis in fibroblasts?
What collagens are non-fibrillar (fibril-associated)?
Type IV, IX, X
What do fibril associated (non-fibrillar) collagens do?
They regulate the organisation of fibrillar collagens in tissues
What are the symptoms and cause of Ehlers-Danlos syndrome?
Stretchy skin and loose joints (joint hypermobility)
Due to mutations affecting collagen production in connective tissue
How is the tensile strength of collagen established?
The fibres are held in parallel bundles which resist the tensile force in one direction
What are collagen alpha chains synthesized from?
Longer precursors called pro-alpha chains
What is cleaved from procollagen to make collagen in the case of fibrillar collagens?
N-terminal propetide and C-terminal propeptide
Where is type IV collagen found?
In all basement membranes
What type of network does type IV collagen form?
A sheet-like network
What happens to the N and C terminus in type IV collagen?
It remains intact as type IV is non-fibrillar
What does uncleaved N and C termini allow type IV collagen to do?
Interact with other collagen molecules to form a network of collagen, acting as a basement membrane
What is another name for basement membranes?
Basal lamina
What is the basement membrane?
A thin, flexible mat of extra-cellular matrix which the epithelial cell sheet sits on top of
What structures are surrounded by basement membrane?
Muscle, peripheral nerve and fat cells
What do basement membranes form a part of the kidney?
They form a key part of the filtration unit as the glomerular basement membrane
What is diabetes nephropathy?
Disorder where there is an accumulation of ECM leading to highly thickened basement membrane
This results in less renal filtration and can cause renal failure
What is Alport Syndrome?
Where mutations in collage IV result in an abnormally laminated glomerular basement membrane
This is associated with progressive loss of kidney function and hearing loss
What helps to limit the extent of elastic fibres stretching?
The elastic fibres are interwoven with collagen
What do elastic fibres consist of?
A core made up of elastin protein, surrounded by microfibrils which are rich in the protein fibrillin
What amino acid side chains are covalently cross linked in elastin?
Lysine
Describe the structure of elastin fibres
Elastin consists of two types of segments that alternate along the polypeptide chain:
Hydrophobic regions and an alpha-helical region that is rich in lysine and alanine – many of these lysin side chains are covalently crosslinked
Where is fibrillin found?
In the microfibrils which surround the elastin core
Mutations in fibrillin-1 are associated with what syndrome?
Marfans Syndrome
What are patients with Marfans syndrome pre-disposed to and what symptoms do they have?
Predisposed to aortic ruptures
Long spiderlike fingers and long slender limbs
How are ECM proteins able to multi-function?
They have a modular structure
What is meant by multi-adhesive modular proteins?
The proteins can bind various matrix components and cell-surface receptors
What is the shape of the laminin molecule?
A cross shape due to the presence of three chains - alpha, beta and gamma
Are laminins large or small proteins?
Large
Which surface cell receptors can laminins interact with?
Integrins and dystroglycans
What structure can laminins self associate as part of?
Basement membrane matrix
What other matrix components can laminins interact with?
Type IV collagen, nidogen, proteoglycans
What mutation of laminin results in congenital muscular dystrophy?
Absence of the alpha-2 chain in laminin-2
What are some symptoms of congenital muscular dystrophy?
Hypotonia (decreased muscle tension)
Generalised muscle weakness
Deformities of the joints
What are the two forms which fibronectins can exist as?
Insoluble fibrillar matrix or soluble plasma proteins
How are different forms of fibronectins formed?
Alternate splicing of mRNAs
What do fibronectins do?
Regulate cell surface adhesion
Regulate migration in a variety of processes, notably embryogenesis
Tissue repair
Explain the multi-domain structure of fibronectin
Several domains are linked by disulphide bonds
Several collagen and cell binding sites are present
How is fibronectin involved in the binding of collagen fiber to actin filament?
Fibronectin binds a collagen fibre and the integrin receptor on the other side, providing linkage between the ECM and cytoskeleton
Adaptor protein binds to the other end of the integrin receptor, and an actin filament binds to the adaptor protein
What is a proteoglycan?
Core proteins which are covalently bonded to one or more glycosaminoglycan chains
What proteoglycan is considered small and leucine rich?
Decorin
What is the name of a cell surface proteoglycan?
Syndecans
What is a GAG chain?
Glycosaminoglycan chain
What makes up a GAG chain?
Repeating disaccharide units with one of the two sugars being an amino sugar
What is an amino sugar?
A sugar in which one of the hydroxyl group is replaced with a amine group
What has to happen to the GAG chain in order for it to carry a high negative charge?
Has to be sulfated or carboxylated
What effect does the high negative charge of the GAG chain result in?
It attracts clouds of cations, including Na+, which therefore pulls water into the ECM through osmosis
Why does cartilage have a high tensile strength?
Cartliage has ECM rich in collagen and glycosaminoglycan chains trapped in mesh
Thus the balance of swelling pressure is negated by the tension in the collagen fibres
What are the four groups of GAG chains?
Hyaluronan
Chondroitin sulfate
Heparan sulfate
Keratan sulfate
How is hyaluronan produced?
It is spun out directly from an enzyme embedded in the plasma membrane
How is hyaluronan distinct from other GAG chains?
It is simply a carbohydrate chain without a core protein and is unsulfated
Why can hyaluranan chains occupy large volumes?
Because it can undergo a very high degree of polymerisation, which creates very large molecules
What is the role of hyaluronan in the synovial fluid of joints?
Protects the cartilaginous surfaces from damage
Where else is hyaluornan found apart from in the synovial fluid of joints?
Vitreous humour of the eye
What is a major constituent of the cartilage ECM?
Aggrecan
Aggrecan is highly sulphated. What effect does this have?
Increases their negative charge which attracts cations that are osmotically active - leads to large amounts of water being retained by the negatively charged environment
what is osteoarthiritis?
an erosive disease resulting in excessive ECM degradation
What is lost with osteoarthiritis?
The cushioning properties of cartilage over the end of bones
What leads to a loss of aggrecan fragments to the synovial fluid?
The cleavage of aggrecan by aggrecanases and metalloproteinases - this increases with age
How do fibrotic diseases arise?
They are as a result of excessive production of fibrous connective tissue
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
