Extracellular matrix Flashcards
What is an extracellular matrix?
A complex network of proteins and carbohydrates filling spaces between cells
What is the extracellular matrix made up of?
both fibrillar and non-fibrillar components
What are the 4 key functions of the extracellular matrix?
- Provides physical support
- Determines the mechanical and physicochemical properties of the tissue
- Influences the growth,
adhesion and differentiation status of the cells and tissues with which it interacts - Essential for development, tissue function and organogenesis
What is connective tissue made up of?
Extracellular matrix and component materials
components: versican and laminin
What are connective tissues made up of?
Collagens
Type I, II, III (fibrillar)
Type IV (basement membrane)
Multi-adhesive glycoproteins
Fibronectin, Fibrinogen
Laminins (basement membrane)
Proteoglycans
Aggrecan, Versican, Decorin
Perlecan (basement membrane)
What are the human disorders resulting from ECM abnormalities?
- Gene mutations affecting matrix proteins
- . Gene mutations affecting ECM catabolism
- . Fibrotic disorders due to excessive ECM deposition
- Disorders due to excessive loss of ECM
What are collagens?
- Family of fibrous proteins
- Major proteins in bone, tendon and skin
( most abundant proteins)
How are collagen fibrils aligned in the skin as well as mature bone and cornea?
successive layers nearly at right angles to each other
These tissues resist tensile force in all directions
molecular arrangements of collagen fibres?
Each collagen molecule comprises three α chains, forming a triple helix.
Can be composed of one or more different α chains
What is the composition of collagen I ?
has chains from two different genes - its composition is [α1(I)]2 [α2(I)]
What is the composition of collagen II and III ?
have only one chain type – their compositions are, therefore, [α1(II)]3 and [α1(III)]3
What is the arrangement of an α chain?
characteristic gly-x-y repeat
x- often proline) (y- often hydroxyproline
How are collagen fibres assembled?
one α chain –>
3 α chains –>
collagen fibril –>
collagen fibre
What do all newly synthesised collagen chains have?
non-collagenous domains at N- and C-termini.
but after secretion they are usually removed
Collagen biosynthesis pathway?
Procollagen –>
Collagen –>
Fibril formation –>
Cross-linking
Fibrillar collagen biosynthesis
synthesis of pro-a chain –>
hydroxylation of selected prolines and lysines –>
glycosylation of selected hydroxylysines –>
self-assembly of the pro-a chains –>
procollagen triple-helix formation –>
secretion (through secretory vesicles or into the ER/ Golgi compartment) –> (procollagen molecule)
cleavage of propeptides –>
(collagen molecule) self-assembly into fibril –>
(collagen fibril) aggregation of collagen fibrils to form a collagen fibre
What does crosslinking provide?
tensile strength and stability
What is involved in cross-linking?
Both lysine and hydroxy-lysine residues are involved
What is the extent of cross-links?
the type and extent is tissue specific and changes with age
What do prolyl and lysyl hydroxylases require?
Fe2+
vitamin C
contribute to interchain hydrogen bond formation
What does Vitamin C deficiency result in?
underhydroxylated collagens, with dramatic consequences for tissue stability (scurvy)
What is ehlers-danlos syndromes (EDS)?
a group of inherited connective tissue disorders whose symptoms include stretchy skin and loose joints
What do mutations in collagen affect?
- collagen production
- collagen structure
- collagen processing
Not all collagen form fibrils
Fibril-associated collagens associate with fibrillar collagens and regulate the organisation of collagen fibrils
What is the basement membrane formed from?
flexible-sheet like multilayered network
type IV collagen
What is the role of basement membranes?
regulators of tissue function
What are basement membranes?
are flexible, thin mats of extracellular matrix underlying epithelial sheets and tubes
- contain a distinct repertoire of collagens, glycoproteins and proteoglycans
What do basement membranes surround?
muscle, peripheral nerve and fat cells and underlie most epithelia
What do they form an important part of in the kidney?
filtration unit as the Glomerular basement membrane (GBM)
What is the disorder diabetic nephropathy?
there is an accumulation of extracellular matrix leading to a highly thickened basement membrane. This restricts renal filtration and can lead to renal failure
What is Alport syndrome?
mutations in collagen IV result in an abnormally split and laminated GBM which is associated with a progressive loss of kidney function and also hearing loss
Are elastic fibres usually found by themselves?
no, collagen and elastic fibres are interwoven to limit the extent of stretching
What do elastic fibres consist of?
a core made up of the protein elastin, and microfibrils, which are rich in the protein fibrillin
What is Marfan’s syndrome?
Mutations in the protein fibrillin-1
skeletal, ocular, and cardiovascular systems are affected
What is elastin?
unusual protein consisting of two types of segments that alternate along the polypeptide chain: hydrophobic regions, and α-helical regions rich in alanine and lysine
-Many lysine side chains are covalently cross-linked
What are some examples of multi-adhesive glycoproteins?
Laminins (associated with basement membranes)
fibronectin
How are extracellular matrix proteins organised?
- Most ECM proteins are very large
- composed of characteristic protein domains of 50-200 amino acids
- multifunctional: modular structure
- multi-adhesive, binding various matrix components and cell-surface receptors
What are lamins?
heterortrimeric proteins made up of an α chain, a β chain and a γ chain, which form a cross shaped molecules
- very large proteins
What is the role of lamilins?
- multi-adhesive proteins which can interact with a variety of cell surface receptors including integrins and dystroglycan
- self-associate as part of the basement membrane matrix
- interact with other matrix components
What are the diseases from typical mutations in lamilin?
muscular dystrophy and epidermolysis bullosa
What are fibronectins?
a family of closely related glycoproteins of the extracellular matrix which are also found in body fluids
- multi-adhesive proteins
How can fibronectins exist?
insoluble fibrillar matrix or as a soluble plasma protein
From how many genes are fibronectins derived?
from a single gene, with alternate splicing of mRNAs giving rise to the different types
What are the bonds in laminin?
large multidomain molecule linked together by disulphide bonds
What are the roles of laminins?
regulating cell adhesion and migration in a variety of processes, notably embryogenesis and tissue repair
- promote blood clotting
What does laminin link to?
between the matrix and cytoskeleton
What are proteoglycans?
core proteins to which are covalently attached one or more glycosaminoglycan (GAG) chains
What are GAG chains made up of?
repeating disaccharide units with one of the two sugars being an amino sugar
- many are sulfated or carboxylated, and as a result carry a high negative charge
What does the negative charge on GAG chains attract?
a cloud of cations including Na+, resulting in large amounts of water being sucked into the extracellular matrix
What are the different proteoglycan families? (4)
- Basement membrane proteoglycans
- Aggregating proteoglycans
- Small leucine-rich proteoglycans
- Cell surface proteoglycans
What is cartilage made up of?
matrix rich in collagen with large quantities of GAGs trapped within the meshwork
What are the 4 groups of GAG chains?
- Hyaluronan
- Chondroitin sulfate and dermatan sulfate
- Heparan sulfate
- Keratan sulfate
What is hyaluronan? (hyaluronic acid)
a carbohydrate chain without a core protein
(is distinct form the other GAGs)
It is unsulfated and made up of repeating disaccharides which can number up to 25,000 sugars
Where is hyaluronan found?
in the extracellular matrix of soft connective tissues
– vitreous humour of the eye and in synovial fluid of joints
What is aggrecan?
major constituent of the cartilage extracellular matrix
What is the structure of aggrecan?
the GAGs are highly sulfated, increasing their negative charge
- also contain large numbers of negatively carboxyl groups
What do the multiple negative charges on aggrecan attract?
cations such as Na+ that are osmotically active –>large quantities of water retained by the highly negatively charged environment
Why is aggrecan perfectly suited to resist compressive forces?
Under compressive load, water is given up, but regained once the load is reduced
What are the disorders resulting from ECM abnormalities?
osteoarthritis
fibrotic disease
What is osteoarthritis?
an erosive disease resulting in excessive extracellular matrix degradation
(loss of cartilage)
What happens with aggrecan with age?
it is cleaved by aggrecanases and metalloproteinases
–> loss of aggrecan fragments to the synovial fluid
What is fibrotic disease?
a result of an excessive production of fibrous connective tissue
