Extracellular Matrix Flashcards
What is the ECM?
Complex network of proteins and carbohydrates
—> filling spaces between cells
Both fibrillar and non fibrillar components
What are the key functions oft he ECM?
Provide physical support
Determines mechanicals and physio chemical properties of tissue
Influence growth, adhesion and differentiation statuts of cells and tissues
Essential for development, tissue function and organogenesis
What is the connective tissue?
ECM + component cells
What are the components of connective tissues?
Collagens
Multi-adhesive glycoproteins
Proteoglycans
Examples a of collagens.
Type I, II, III —> fibrillar
Types IV —> non-fibrillar —> basement membrane
Examples of multi-adhesive glycoproteins.
Fibronectin, fibrinogen
Laminins —> basement membrane
Examples of proteoglycans.
Aggrecan, versican, decorin
Perlecan —> basement membrane
What are the different types of connective tissue?
Tendon and skin —> tough and flexibles
Bone —> hard and dense
Cartilage —> resilient and shock-absorbing
How do the different types of connective tissue come about?
Difference in ECM components
What 2 things do gene mutations affect in the ECM that can cause human disorders?
ECM proteins
ECM catabolism (hoe ECM molecules are broken down)
Examples of gene mutations affecting matrix proteins.
Osteogenesis imperfecta
Marfan’s syndrome —> fibrillin 1
Alport’s syndrome —> type IV collagen (alpha 5)
Epidermolysis Bullosa
Cognitive Muscle Dystrophy —> laminin 2 (alpha 2 chain)
Gene mutations affecting ECM catabolism examples.
Hurler’s syndrome —> L-alpha-iduronidase
Fibrotic disorders due to excessive ECM deposition.
Liver fibrosis —> cirrhosis
Kidney fibrosis —> diabetic nephropathy
Lung fibrosis —> idiopathic pulmonary fibrosis (IPF)
Disorders due to excessive loss of ECM
Osteoarthritis
What are collagens?
Family of fibrous proteins
Major proteins in bone, tendon and skin
Most abundant proteins in mammals
What is the alignment of collagen fibres like?
Successive layers nearly at right angles
—> resist tensile force in all direction
How many types of collagen exist in humans and how many genes encode them?
28 types
42 gene
What is the structure of collagen?
3 alpha chains —> from triple helix
What is the composition of Type I collagen?
[alpha1(I)]2 [alpha2(I)]
Heterotrimer
What ois the composition of Type II and III collagen?
[alpha1(II)]3
[alpha1(III)]3
Homotrimers
What is the structure of the triple helix?
Each chain: gly-x-y repeat —> often x proline y hydroxyproline
Chain form a left-handed helix
Three alpha chains (approx 1000 amino acids) pack together to form stiff triple helical structure
Why must every third position in a collagen triples helix alpha chain need to be glycine?
Glycine is smallest amino acid so is small enough to occupy the interior of the helices with its H side chain
—> helix can pack closely together
How are collagen fibres assembled?
1 alpha chain
3 alpha chains (helix)
Collagen fibril
Collagen fibre
What are the steps in fibrillar collagen biosynthesis?
- Synthesis of pro-alpha chain
- Post translational modifications
—> hydroxylation of selected prolines ans lysines
—> glycosylation of some hydroxylysines - Self-assembly of 3 pro-alpha chains into procollagen triple helix
- Procollagen packed into secretory vesicle (or transferred into cytoplasm)
- Secreted out of cell
- End termini cleaves
- Self-assembly into fibril
- Aggregation of collagen fibrils to form a collagen fiber
What function do covalent cross-links in collagen have?
Provide tensile strength and stability
Type and extent —> tissue specific and changes with age
Where do the covalent cross-links in collagen happen?
Lysine and hydroxy-lysine residues
Why is lysine and proline hydroxylation important?
Contributes to interchain hydrogen bond formation
What happens in Scurvy?
Vit C deficiency —> under-hydroxylated collagens
—> dramatic effects on tissue stability
What does lysine and proline hydroxylation require?
Fe2+ and Vit C
What is Ehlers-Danlos syndrome (EDS)?
Inherited connective tissue disorder
- fargile skin and blood vessels
- hyper-mobile joints
- stretchy skin
- loose joints
Due to mutations in collagen which affect:
—> production
—> structure
—> processing
What are the non-fibrillar collagens?
Types IX and XII
Types IV
What do types IX and XII collagen do?
Associate with fibrillar collagens
—> regulate organisation of collagen fibrils
What does Type IV collagen do?
Network forming collagen —> in all basement membranes
N and C termini not cleaved
—> domains interact with one another to form a network
What is the basement membrane?
Flexible, thin mats of ECM underlying epithelial sheets and tubes containing collagens, glycoproteins and proteoglycans
What happens in Diabetic Nephropathy?
Accumulation of ECM —> highly thickened basement membrane
—> restricts renal filtration —> renal failure
What happens in Alpert syndrome?
Mutation in collagen IV
—> abnormally split and laminated GBM
—> progressive loss of kidney function
What are laminins?
Heterotrimeric protein —> alpha, beta and gamma chain
What is the purpose of laminins?
Multi-adhesive protein —> interacts w/ variety of cell surface receptors —> integrin and dystroglycan
Can self-associate as part of basement membrane matrix
Can also interact with matrix components
—> type IV collagen, nidogen and proteoglycans
What is Congenital muscular dystrophy
Absence of alpha2 chain in laminin 2
Decreases adhesion and basement membrane stability?
Muscle weakness and degeneration
What are elastic fibres made up of?
Ealastin core and surrounded by microfibrils rich in protein fibrillin
Woven to limit the extent of stretching
What is the function of elastic fibres?
Provide elasticity to tissues
What is fibrillin important for?
The integrity of elastic fibres
What is Marfan’s syndrome?
Mutation in the fibrillin-1 protein
Aberrant thickening of the aortic worth fragmentation and disarray of elastic fibres
—> can be predisposed to aortic ruptures
What is elastin?
Small protein arranged in a random coil of alternating hydrophobic and hydrophilic domains
Lysine residues cross linked during formation of mature elastin
What are fibronectins?
Dimmer with many diff domains
—> disulphide link at C terminal
Derived from a single gene —> alternate splicing of mRNAs give rise to different types
—> insoluble fibrillar matrix
—> soluble plasma protein
What is the function of fibronectins?
Regulate:
- cell adhesion
- migration in embryogenesis
- tissue repair
Important for:
- wound healing
- helping promote blood clotting
Bind multiple ligand and cell receptors
What are proteoglycans?
Core proteins w/ covalently attached glycosaminoglycan (GAG) chains
What are GAG chains made up of?
Repeating disaccharide units w/ 1 or 2 sugars being an amino sugar
Sulfation/craboxylation can increase negative charge
What are the main GAG varieties?
Hyaluronan
Chondroitin sulfate/Fermat an sulfate
Heparan sulfate
Keratan sulfate
What is hyaluronan?
Carbohydrate chain w/out a core protein
Unsulfated
Found in highly viscous tissue
Key role in protecting the cartilaginous surface from damage
What is aggrecan?
Major constituent of cartilage
Perfectly suited to resist compressive forces
—> water given up but regained once load is reduced
What does Osteoarthritis do?
Erosive disease resulting in loss of ECM vis degradation
Cushioning properties of cartilage over bone ends is lost
—> aggrecan cleavage by aggrecan AES’s and metalloproteinases
