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PoM > extracellular matrix > Flashcards

extracellular matrix Flashcards

1
Q

what is the extracellular matrix?

A

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

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2
Q

what 2 types of role does the extracellular matrix carry out?

A

architectural (mechanical stability)

instructional (influences cell behaviour)

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3
Q

the extracellular matrix is essential for what 3 things?

A

development

tissue function

organogenesis

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4
Q

what are the 3 key functions of the extracellular matrix?

A

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

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5
Q

what kind of tissues are particularly rich in extracellular matrix?

A

connective tissues (extracellular matrix and component cells)

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6
Q

what are the 3 main components of the extracellular matrix?

A

collagens

multi-adhesive glycoproteins

proteoglycans

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7
Q

what are some examples of the different types of collagens?

A

Type I, II, III (fibrillar)

Type IV (basement membrane)

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8
Q

what are some examples of the different types of multi-adhesive glycoproteins?

A

fibronectin, fibrinogen, laminins (basement membrane)

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9
Q

what are some examples of the different types of proteoglycans?

A

aggrecan, versican, decorin, perlecan (basement membrane)

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10
Q

how does each matrix component interact with cellular components?

A

via specific cell surface receptors

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11
Q

how do connective tissues vary in their properties and why?

A

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
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12
Q

what are collagens?

A

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

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13
Q

what is the structure of a collagen molecule?

A

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

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14
Q

what is the structure and composition of Type I collagen?

A

chains from 2 genes

heterotrimer

composition [α1(I)]2 [α2(I)]

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15
Q

what is the structure and composition of Type II collagen?

A

only 1 chain type

homotrimer

composition [α1(II)] 3

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16
Q

what is the structure and composition of Type III collagen?

A

only 1 chain type

homotrimer

composition [α1(III)] 3

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17
Q

describe the primary sequence of collagen proteins.

A

characteristic glycine-x-y repeat

x is often proline

y is often hydroxyproline

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18
Q

why is it important that every third position in the primary sequence of collagen proteins is glycine?

A

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)

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19
Q

how are covalent crosslinkages in collagen formed?

A

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)

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20
Q

what do intermolecular and intramolecular crosslinks in collagen do and which amino acids are involved?

A

provide tensile strength and stability

lysine and hydroxylysine residues involved

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21
Q

when does crosslinking take place in collagen formation?

A

only after collagen has been secreted

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22
Q

how does vitamin C deficiency lead to scurvy?

A

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

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23
Q

how is collagen biosynthesised?

A

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

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24
Q

how do tropocollagen molecules allow tensile strength to occur?

A

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)

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25
Q

what do fibril-associated collagens do?

A

regulate organisation of collagen fibrils in tissues

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26
Q

what are Ehlers-Danlos syndromes (EDS)?

A

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)

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27
Q

what type of collagen is type IV collagen?

A

non fibrillar

forms sheet like networks rather than fibrils

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28
Q

where is type IV collagen present?

A

all basement membranes

network structure is an essential component

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29
Q

describe the structure of collagen IV networks.

A

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

30
Q

what are basement membranes/basal laminae (BMs)?

A

flexible, thin mats of extracellular matrix underlying epithelial sheets and tubes

highly specialised extracellular matrix containing a specific combination of collagens, glycoproteins and proteoglycans

31
Q

where are basement membranes found?

A

surrounding muscle, peripheral nerve and fat cells

underlie most epithelia

32
Q

where are basement membranes found in the kidneys?

A

glomerular basement membrane (GBM)

33
Q

what happens in the disorder diabetic nephropathy?

A

accumulation of extracellular matrix leads to thickened basement membrane

thickened basement membrane restricts renal filtration and can lead to renal failure

34
Q

what happens in Alport syndrome?

A

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

35
Q

why are elastic fibres important?

A

elasticity of tissues such as skin, blood vessels and lungs

36
Q

what is the relationship between collagen and elastic fibres?

A

often interwoven

limits extent of stretching

37
Q

what is the structure of an elastic fibre?

A

core made up of the protein elastin

surrounded by microfibrils, rich in the protein fibrillin, upon which the integrity of the fibres depends

38
Q

how is Marfan’s syndrome caused and how does it manifest?

A

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

39
Q

what is the structure of elastin?

A

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

40
Q

what does a protein having a modular architecture mean?

A

the protein is composed of characteristic protein domains

41
Q

what is the structure of most ECM proteins?

A

very large

modular architecture that allows multifunctionality

42
Q

what is the function of many large modular proteins in the ECM?

A

multi adhesive

binds many matrix components and cell surface receptors

43
Q

what are laminins?

A

type of multi-adhesive glycoprotein

very large

44
Q

what is the structure of a laminin?

A

heterotrimeric - made up of an α chain, a β chain and a γ chain

chains form cross shaped molecules

45
Q

what is the function of laminins?

A

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)

46
Q

what are 2 inherited diseases that arise from mutations in specific chains of laminins?

A

muscular dystrophy

epidermolysis bullosa

47
Q

how does congenital muscular dystrophy arise and what are the symptoms?

A

absence of the α2 chain in laminin 2

symptoms include hypotonia (abnormally decreased muscle tension), generalised weakness and deformities in the joints

48
Q

what are fibronectins?

A

family of closely related glycoproteins of the extracellular matrix, also found in bodily fluids

49
Q

what are the 2 forms of existence of fibronectins?

A

insoluble fibrillar matrix

soluble plasma protein

50
Q

from where are fibronectins derived?

A

a single gene

alternate splicing of mRNA gives rise to different types

51
Q

describe the structure of fibronectins.

A

multi adhesive proteins

large multi domain molecule linked together by disulphide bonds

52
Q

what are the roles of fibronectins?

A

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

53
Q

what are proteoglycans?

A

core proteins

covalently attached to one or more glycosaminoglycan (GAG) chains

54
Q

how are proteoglycan families grouped?

A

based on structural and functional characteristics

55
Q

what are the 4 different types of proteoglycan? give an example of each.

A

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

56
Q

what is the structure of a GAG (glycosaminoglycan) chain?

A

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

57
Q

what is an amino sugar?

A

a sugar where a hydroxyl group is replaced with an amine group

58
Q

what is the structure of cartilage like and how does this help function?

A

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

59
Q

how many GAG chains can be attached to a proteoglycan?

A

small proteoglycans have a single GAG chain attached

some large one carry up to 100

60
Q

GAG chains are grouped into 4 main groups based on what?

A

the repeating disaccharide unit

61
Q

what are the 4 main groups of GAG chain, based on the repeating disaccharide unit?

A

hyaluronan

chondroitin sulfate and dermatan sulfate

heparan sulfate

keratan sulfate

62
Q

how is hyaluronan/hyaluronic acid produced?

A

spun out directly from an enzyme embedded in the plasma membrane

63
Q

how are GAGs (apart from hyaluronan) produced?

A

synthesised and attached to their core proteins in the ER and Golgi inside the cells

64
Q

where is hyaluronan/hyaluronic acid found?

A

ECM of soft connective tissues

65
Q

what is the structure of hyaluronan/hyaluronic acid?

A

carbohydrate chain, no core protein (distinct from other GAGs)

unsulfated

made up of repeating disaccharides (up to 25 000 sugars)

66
Q

why do hyaluronan chains occupy a relatively large volume and why is this important?

A

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)

67
Q

what role does hyaluronan/hyaluronic acid play in the synovial fluid of joints?

A

helps protect cartilaginous surface from damage

68
Q

what is hyaluronan/hyaluronic acid?

A

GAG chain

69
Q

what is aggrecan?

A

proteoglycan

major cartilage matrix constituent

70
Q

what is the structure of aggrecan and how does this help its function?

A

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

71
Q

what is osteoarthritis?

A

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

72
Q

why do fibriotic diseases arise?

A

result of excessive production of fibrous connective tissue

PoM (42 decks)

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