extracellular matrix Flashcards
what is the extracellular matrix?
complex network of macromolecules (proteins and carbohydrates) deposited by cells
made up of fibrillar and non-fibrillar components
after being deposited, it becomes immobilised outside the cells and fills the spaces between cells
what 2 types of role does the extracellular matrix carry out?
architectural (mechanical stability)
instructional (influences cell behaviour)
the extracellular matrix is essential for what 3 things?
development
tissue function
organogenesis
what are the 3 key functions of the extracellular matrix?
providing physical support
determining mechanical and physicochemical properties of the tissue
influencing the growth, adhesion and differentiation status of the cells and tissues with which it interacts
what kind of tissues are particularly rich in extracellular matrix?
connective tissues (extracellular matrix and component cells)
what are the 3 main components of the extracellular matrix?
collagens
multi-adhesive glycoproteins
proteoglycans
what are some examples of the different types of collagens?
Type I, II, III (fibrillar)
Type IV (basement membrane)
what are some examples of the different types of multi-adhesive glycoproteins?
fibronectin, fibrinogen, laminins (basement membrane)
what are some examples of the different types of proteoglycans?
aggrecan, versican, decorin, perlecan (basement membrane)
how does each matrix component interact with cellular components?
via specific cell surface receptors
how do connective tissues vary in their properties and why?
different types of collagen
different arrangements of oriented collagen
presence/absence of different ECM components
allows different functions where needed:
- vitreous humour needs to be soft and transparent
- tendon and skin need to be tough and flexible
- bone needs to be hard and dense
- cartilage needs to be resilient and shock absorbent
what are collagens?
family of fibrous proteins found in all multicellular organisms
major protein components of bone, tendon and skin
at least 28 different types in humans, components encoded by 48 different genes
what is the structure of a collagen molecule?
3 α chains
can be a homotrimer or a heterotrimer
triple helix formed
in fibrillar collagens, each chain is approx. 1000 amino acids long, forming a left handed helix
what is the structure and composition of Type I collagen?
chains from 2 genes
heterotrimer
composition [α1(I)]2 [α2(I)]
what is the structure and composition of Type II collagen?
only 1 chain type
homotrimer
composition [α1(II)] 3
what is the structure and composition of Type III collagen?
only 1 chain type
homotrimer
composition [α1(III)] 3
describe the primary sequence of collagen proteins.
characteristic glycine-x-y repeat
x is often proline
y is often hydroxyproline
why is it important that every third position in the primary sequence of collagen proteins is glycine?
to form a stiff triple helical structure
glycine is the only amino acid small enough to occupy the interior when the helix is formed (since the side chain is only an H atom)
how are covalent crosslinkages in collagen formed?
lysine and hydroxylysine residues are involved
modified in a similar way to proline in formation of interchain hydrogen bonds (hydroxylation of proline is a post translational modification that contributes to hydrogen bond formation)
what do intermolecular and intramolecular crosslinks in collagen do and which amino acids are involved?
provide tensile strength and stability
lysine and hydroxylysine residues involved
when does crosslinking take place in collagen formation?
only after collagen has been secreted
how does vitamin C deficiency lead to scurvy?
vitamin C is a co factor for prolyl hydroxylase and lysyl hydroxylase enzymes; necessary for function
therefore vitamin C deficiency results in underhydroxylated collagens
negatively impacts tissue stability - i.e scurvy
how is collagen biosynthesised?
normal pathway for secreted protein
however, collagen α chains are synthesised as longer precursors (pro-α chains) by ribosomes attached to the ER
pro-α chains undergo a series of covalent modifications, fold into triple-helical procollagen molecules before release from cells
cleavage, fibril formation and cross linking occurs between molecules
how do tropocollagen molecules allow tensile strength to occur?
staggered arrays of tropocollagen molecules form fibrils which arrange to form collagen fibres
tensile strength is provided by the fibres being in parallel bundles (resist tensile force in one direction)
what do fibril-associated collagens do?
regulate organisation of collagen fibrils in tissues
what are Ehlers-Danlos syndromes (EDS)?
group of inherited connective tissue disorders
symptoms include stretchy skin and loose joints
several can arise due to mutations in collagen (impact collagen production, structure or processing)
what type of collagen is type IV collagen?
non fibrillar
forms sheet like networks rather than fibrils
where is type IV collagen present?
all basement membranes
network structure is an essential component
describe the structure of collagen IV networks.
sheet like network
type IV molecules can associate laterally between triple helical segments
can also associate head to head and tail to tail between globular domains to give dimers, tetramers and higher order complexes
what are basement membranes/basal laminae (BMs)?
flexible, thin mats of extracellular matrix underlying epithelial sheets and tubes
highly specialised extracellular matrix containing a specific combination of collagens, glycoproteins and proteoglycans
where are basement membranes found?
surrounding muscle, peripheral nerve and fat cells
underlie most epithelia
where are basement membranes found in the kidneys?
glomerular basement membrane (GBM)
what happens in the disorder diabetic nephropathy?
accumulation of extracellular matrix leads to thickened basement membrane
thickened basement membrane restricts renal filtration and can lead to renal failure
what happens in Alport syndrome?
mutations in collagen IV
this results in an abnormally split and laminated GBM
this type of GBM damage is associated with progressive loss of kidney function and hearing loss
why are elastic fibres important?
elasticity of tissues such as skin, blood vessels and lungs
what is the relationship between collagen and elastic fibres?
often interwoven
limits extent of stretching
what is the structure of an elastic fibre?
core made up of the protein elastin
surrounded by microfibrils, rich in the protein fibrillin, upon which the integrity of the fibres depends
how is Marfan’s syndrome caused and how does it manifest?
mutations in fibrillin-1 protein (important component of microfibrils, which give elastic fibres integrity)
diverse manifestation involving (primarily) skeletal, ocular and cardiovascular systems; individuals can also be predisposed to aortic ruptures
what is the structure of elastin?
2 types of segments that alternate along the polypeptide chain:
- hydrophobic regions
- a helical regions rich in alanine and lysine
many lysine side chains are covalently cross linked
what does a protein having a modular architecture mean?
the protein is composed of characteristic protein domains
what is the structure of most ECM proteins?
very large
modular architecture that allows multifunctionality
what is the function of many large modular proteins in the ECM?
multi adhesive
binds many matrix components and cell surface receptors
what are laminins?
type of multi-adhesive glycoprotein
very large
what is the structure of a laminin?
heterotrimeric - made up of an α chain, a β chain and a γ chain
chains form cross shaped molecules
what is the function of laminins?
multi adhesive proteins
interact with many cell surface receptors (including integrins and dystroglycan)
can self-associate as part of the basement membrane matrix
can also interact with other matrix components (e.g collagen IV, nidogen, proteoglycans)
what are 2 inherited diseases that arise from mutations in specific chains of laminins?
muscular dystrophy
epidermolysis bullosa
how does congenital muscular dystrophy arise and what are the symptoms?
absence of the α2 chain in laminin 2
symptoms include hypotonia (abnormally decreased muscle tension), generalised weakness and deformities in the joints
what are fibronectins?
family of closely related glycoproteins of the extracellular matrix, also found in bodily fluids
what are the 2 forms of existence of fibronectins?
insoluble fibrillar matrix
soluble plasma protein
from where are fibronectins derived?
a single gene
alternate splicing of mRNA gives rise to different types
describe the structure of fibronectins.
multi adhesive proteins
large multi domain molecule linked together by disulphide bonds
what are the roles of fibronectins?
interact with cell surface receptors and other matrix molecules
important roles in regulating cell adhesion in many processes (e.g embryogenesis, tissue repair)
important in wound healing - help to promote blood clotting
form a mechanical continuum with actin cytoskeleton in many cell types
integrin receptors at the cell surface provide linkage between matrix and cytoskeleton
what are proteoglycans?
core proteins
covalently attached to one or more glycosaminoglycan (GAG) chains
how are proteoglycan families grouped?
based on structural and functional characteristics
what are the 4 different types of proteoglycan? give an example of each.
basement membrane proteoglycans
e.g perlecan
aggregating proteoglycans
(interact with hyaluronan)
e.g aggrecan
small leucin-rich proteoglycans
e.g decorin
cell surface proteoglycans
e.g syndecans 1-4
what is the structure of a GAG (glycosaminoglycan) chain?
repeating disaccharide units
one of the two sugars in the disaccharide unit is an amino sugar (sugar where a hydroxyl group is replaced with an amine group)
many GAGs are sulfated or carboxylated (therefore high negative charge)
negative charge attracts a cloud of cations including Na+, resulting in large amounts of water being sucked into the extracellular matrix
what is an amino sugar?
a sugar where a hydroxyl group is replaced with an amine group
what is the structure of cartilage like and how does this help function?
matrix rich in collagen
large quantities of GAGs trapped within the meshwork
balance of swelling pressure is negated by tension in collagen fibres
e.g cartilage lining knee joint (synovial cartilage) can support pressures in excess of hundreds of kg/cm²
how many GAG chains can be attached to a proteoglycan?
small proteoglycans have a single GAG chain attached
some large one carry up to 100
GAG chains are grouped into 4 main groups based on what?
the repeating disaccharide unit
what are the 4 main groups of GAG chain, based on the repeating disaccharide unit?
hyaluronan
chondroitin sulfate and dermatan sulfate
heparan sulfate
keratan sulfate
how is hyaluronan/hyaluronic acid produced?
spun out directly from an enzyme embedded in the plasma membrane
how are GAGs (apart from hyaluronan) produced?
synthesised and attached to their core proteins in the ER and Golgi inside the cells
where is hyaluronan/hyaluronic acid found?
ECM of soft connective tissues
what is the structure of hyaluronan/hyaluronic acid?
carbohydrate chain, no core protein (distinct from other GAGs)
unsulfated
made up of repeating disaccharides (up to 25 000 sugars)
why do hyaluronan chains occupy a relatively large volume and why is this important?
hyaluronan/hyaluronic acid can undergo high degrees of polymerisation (in the range of 10 000 disaccharides) - very large molecules created
therefore high viscosity - e.g in the vitreous humour (eye) and synovial fluid (joints)
what role does hyaluronan/hyaluronic acid play in the synovial fluid of joints?
helps protect cartilaginous surface from damage
what is hyaluronan/hyaluronic acid?
GAG chain
what is aggrecan?
proteoglycan
major cartilage matrix constituent
what is the structure of aggrecan and how does this help its function?
highly sulfated GAGs and large numbers of carboxyl groups (increasing negative charge)
negative charges attract cations (e.g Na+) that are osmotically active
therefore lots of water is retained by the highly negatively charged environment
under compressive load, water is given up but is regained once load is reduced - aggrecan in cartilage matrix is suited to resist compressive forces
what is osteoarthritis?
erosive disease
results in excessive ECM degradation (loss of cartilage)
cushioning properties of cartilage over the end of bones is lost
with age, aggregan is cleaved by aggrecanases and metalloproteinases, leading to a loss of aggregan fragments in the synovial fluid
why do fibriotic diseases arise?
result of excessive production of fibrous connective tissue
