Extracellular Maatrix Flashcards
What is the Extracellular matrix
- A complex network of proteins and carbohydrates deposited by and filling spaces between cells
- ## Comprises both fibrillar and non-fibrillar components
Key functions of ECM
Provides physical support
Determines mechanical and physicochemical properties of tissue
Influences growth adhesion and differentiation status if cells
Essential for development tissue function and organogenesis
3 major components of connective tissue
Collagen: Type I,II,III (fibrillar) and type IV (non fibrillar component of basement)
Multi adhesive glycoproteins: fibronectin,fibrinogen,laminins
Proteoglycans: Basement membrane eg perlecan,aggregating proteoglycans eg aagregan,small leucine rich proteoglycans eg decorin
What different types of connective tissue are there
Tendon and skin-tough and flexible
Bone-hard and dense
Cartilage-resilient and shock absorbing
How do different properties of connective tissue come about
Due to difference in ECM components
What are the 2 things gene mutations can affect in ECM to cause human disorders
ECM proteins and ECM catabolism
ECM protein diseases and where mutation is
Osteogenesis imperfecta-type 1 collagen
Marfans syndrome-fibrillin1
Alports syndrome-type IV collagen (alpha5)
Epidermolysis bullosa-laminin 5(in all three chains)
Congenital muscular dystrophy-laminin 2 (alpha 2 chain)
ECM catabolism syndromes
Mucopolysaccharidoses (MPSs) which lead to inability to degrade glycosaminoglycans (GAGs)
e.g. Hurler’s syndrome, leads to build up of ECM molecules
Loss of L-alpha-iduronidase
What does excessive ECM deposition cause
Fibrotic disorders due to excessive production
- Liver fibrosis- caused by cirrhosis
- Kidney fibrosis- caused by diabetic nephropathy
- Lung fibrosis- caused by idiopathic pulmonary fibrosis (IPF)
Disorder due to excessive loss of ECM
osteoarthritis
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
Structure of collagens
3 alpha chains which may be different
Homotrimers are same collagen and heterotrimers are different collagens.
2 a1(1) and 1 a2(1)
Composition of type I and II and III collagens
I: chains from two different genes to [alpha2(I)]
Both only have 1 chain type so compositions are $[alpha1(II)]_3$ and $[alpha1(III)]_3$
They are homotrimers
What is the structure of the triple helix
Gly-X-y in each alpha chain
Gly is glycine
X is usually proline
Y is usually hydroxyproline
Why is glycine always third
The triple helices have to pack together tightly and glycine is smallest amino acid so is small enough to occupy the interior of the helices with it’s H side chain
This gives a stiff triple helix structure in collagen
What happens to the non-collagenous domains at N- and C- termini after secretion in the case of fibrillar collagens?
They are removed
Steps of collagen synthesis
1) synthesis of pro-alpha chains
2) hydroxylation of proline and lysine
3)glycolysatuon of hydroxylisines
4)self assembly of 3 pro alpha chains
5)pro collagen triple helix formation
6)secretion and cleavage
7)aggregation of collagen fibres
- Occurs in Fibroblasts
What two compounds are involved in the cross linking of collagen
Lysine
Hydroxylysine
How do cross links between collagen molecules help with function
Provide tensile strength and stability
How are hydrogen bonds formed between collagen
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 to collagen if there is a vitamin C deficiency
Underhydroxylated collagens, so there are dramatic consequences for tissue stability
Scurvy
Ehlers danlos syndromes
Group of inherited connective tissue disorders whose symptoms include stretchy/elastic skin and loose joints (joint hypermobility)
Several disorders arise due to collagen mutations which negatively affect collagen production, structure and processing
Non fibrillar collagens
Type I,IX- fibril associated collagens that associate with fibrillar collagens to regulate their organisation
Type IV- network forming collagen and is less T in all basement membranes . It has uncleared N and C termini allowing it to interact with ither collagen molecules to form a network of collagen
Basement membranes
Flexible, thin mats of ECM underlying epithelial sheets and tubes containing collagens, glycoproteins and proteoglycans
Found in muscle,peripheral nerve and fat cells
Important in kidney as form part of filtration u it as glomerular basement membrane
What happens in diabetic nephropathy
Accumulation of ECM leading to highly thickened basement membrane which results in less renal filtration and can lead to renal failure
Alpert syndrome
- What happens in Alport syndrome?Mutations in collagen IV result in abnormally split and laminated GBM which is associated with a progressive loss of kidney function and hearing loss
Elastic fibres
Made of core elastin protein and microfibrils rich in fibrillin
Why are collagen and elastic fibres interwoven
To limit extent if stretching
What is fibrillin important for
The integrity if elastic fibres
What condition are mutations in fibrillin1 associated with
Marfans syndrome
Causing long spider like fingers long slender limbs and predisposition to aortic ruptures
Altered fibrillin 1 affects strength of connective tissue
What is elastins structure
Has 2 types of segments that alternate along the polypeptide chain- hydrophobic regions and alpha-helical regions rich in alanine and lysine
Many lysine side chains are covalently cross-linked
Architecture of ECM proteins
Modular- they are composed of characteristic protein domains of 50-200 amino acids- this structure allows for the multifunctionality of ECM proteins
Many large modular proteins are multi-adhesive, binding various matrix components and cell-surface receptors
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Laminins structure
They are heterotrimeric proteins made up of an alpha-chain, beta chain and a gamma-chain
Forming cross chained molecules
Are v large proteins
What makes laminins multi adhesive properties
They can interact with a variety of cell surface receptors including integrins and dystroglycan
Can self-associate as part of the basement membrane matrix but also interact with other matrix components like type IV collagen, nidogen and proteoglycan
What two diseases arise from mutation in one of the chains
- Epidermolysis **bullosa
- Congenital muscular dystrophy, (which mutation causes this and what are 3 major symptoms?)Alpha-2 chain in Laminin-2Hypotonia (abnormally decreased muscle tension), generalised weakness and deformities of the joints
What two forms of fibronectins exist as
Insoluble fibrillar matrix
Soluble plasma matrix
Fibronectin function
Regulate cell adhesion
Migration
Tissue repair
Has disukphide bonds
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
Proteoglycans
Core proteins to which 1 or more glycosamjnoglycan is covalently attached
GAG chains made of disaccharide elevating units
Proteoglycan families
- 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
Cartilage
A matrix rich in collagen with large GAG quantities trapped in mesh
The balance of swelling pressure is negated by tension in the collagen fibres which generates great tensile strength
Cartilage lines the knee joint (synovial cartilage) and can support pressures in hundreds of kg/cm^2
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4 main groups GAG chains are grouped in
Hyaluronjc acid(in core protein)
Heparan sulfate
Keratan sulfate
chondroitin sulfate and dermatan sulfate
Where are GAGs synthesised and attached, and how is hyaluronan distinct?
All are synthesised and attached to their core proteins in ER and Golgi apparatus in cells
Except hyaluronan which is spun out directly from an enzyme embedded in the plasma membrane
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, which leads to large quantities of water retained in highly -ve environment
How is aggrecan perfectly suited to resist compressive forces in cartilage matrix?
Aggrecan is a major constituentof the cartilage extracellular matrix.
Under compressive load, water is given up but is regained once the load is reduced
Suited to resist compressive forces
High negative charges allow this to occur as it attracts Na+ leading water to be retained
Osteoarthritis
Erosive disease resulting in excessive ECM degradation
The cushioning properties of cartilage over bone ends is lost
aggrecan is cleaved by aggrecanases and metalloproteinases which results in a loss of aggrecan fragments to synovial fluid
Congenital muscular dystrophy
Cause by laminins a2 deficiency
Fails to interact with integrity and dystroglycan which is needed for adhesion and basement membrane assembly thus causes muscle weakness
Hylaronan
Glycoaminoglycan
Has no core protein
Found in highly viscous tissue eg vitreous humor of eye
Protects cartilaginous surface from damage
