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POM > Extracellular Matrix > Flashcards

Extracellular Matrix Flashcards

1
Q

What is the extracellular Matrix (ECM)?

A

A complex network of macromolecules (carbohydrates and proteins) deposited by cells

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2
Q

What components does the ECM have?

A

Fibrillar and non-fibrillar components

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3
Q

What are the key functions of the ECM?

A
  1. Provides physical support
  2. Determines mechanical and physiochemical properties of the tissue
  3. Influences growth, adhesion and differentiation status of cells and tissues which it interacts with
  4. Essential for development, tissue function and organogenesis
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4
Q

What does connective tissue contain?

A 
ECM is rich in connective tissue
Contains a complete spectrum of:
- collagens
- multi-adhesive glycoproteins
- proteoglycans with a cellular component
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5
Q

How do matrix compartments interact with cellular compartments?

A

Via cell surface receptors

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6
Q

What are the different collagens found in the ECM?

A 
Type I (bone, skin and tendon)
Type II (cartilage)
Type III (fibrillar, blood vessels and reticulum)
Type IV (basement membrane)
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7
Q

What are the different multi-adhesive glycoproteins found in the ECM?

A

Fibronectin
Fibrinogen
Laminins (basement membrane)

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8
Q

What are the different proteoglycans found in the ECM?

A

Aggrecan
Versican
Decorin
Perlecan (basement membrane)

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9
Q

What are collagens?

A

A family of fibrous proteins found in all multicellular organisms
Most abundant protein in mammals

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10
Q

How many collagen types are there in humans and how many genes encode for them?

A

At least 28

They’re encoded for by 42 different genes

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11
Q

How are collagen fibres aligned?

A

In skin, mature bone and cornea: have successive layers nearly at right angles to each other
Tissues resist force in all directions

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12
Q

How are collagen molecules structured?

A

Each collagen molecule has 3 alpha chains forming a triple helix:
can be a homotrimer or hetrotrimer
can have 1 or more different alpha chains

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13
Q

How is type I collagen structured?

A

Formed from 2 genes
Its a hetertrimer
[α1(I)]2 [α2(I)]

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14
Q

How is type II and III collagen structured?

A

have only 1 chain type
They’re homotrimers
[α1(II)]3 and [α1(III)]3

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15
Q

What is the primary sequence of collagens?

A

Primary sequence of collagen protein contains gly-x-y repeat

x is often proline and y is often hydroxyproline

Every 3rd position must be glycine to give a stiff structure- side chain is just a H so gives close packing

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16
Q

How long is an alpha chain in fibrillar collagen?

A

each alpha chain is approx. 1000 amino acids long forming a left handed helix

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17
Q

How are collagen fibres assembled?

A

One alpha chain joins 2 others to make a triple stranded collagen molecule

Many of these come together to form a collagen fibril

Lots of fibril come together to form a collagen fibre

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18
Q

How is collagen biosynthesised?

A

Collagen alpha chains are synthesised by long precursors called pro-alpha chains by ribosomes attached to the rough ER

Pro-alpha chains undergo a series of covalent modifications and fold into triple helical pro collagen molecules before their release from cells

3 pro-alpha chains collectively form pro collagen chain

This subsequently undergoes cleavage, fibril formation and cross-linkage

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19
Q

Why are cross-links in collagen important?

A

They provide tensile strength and stability

The type and extent of cross-links is tissue specific and changes with age

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20
Q

What is the importance of lysine and proline hydroxylation?

A

Protyl and lysyl hydoxylases require Fe2+ and vitamin C

Lysine and hydroxy-lysine are modified in the formation of covalent cross-linkages

This takes place only after collagen is secreted

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21
Q

What are the implications of vitamin C deficiency?

A

Vit C deficiency results in unhydroxylated collagens with dramatic consequences for stability (scurvy)

This is due to enzymes protyl hydroxylase and lysyl hydroxylase requiring vitamin C asa cofactor for functionality

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22
Q

What is Ehlers- Danlos Syndrome? (EDS)

A

EDS are a group of inherited connective tissue disorders who’s symptoms include stretchy skin and loose joints

23
Q

What can mutations in collagen negatively effect?

A

Collagen production
Collagen structure
Collagen processing

24
Q

What kind of collagens don’t form fibrils?

A

Type IV collagen
It’s present in all basement membranes

Collagen type IV molecules can associate laterally between triple helix segments as well as head to tail and tail to tail between the globular domains to give dimers, tetramers and higher order complexes

25
Q

What is the role of fibril associated collagens?

A

E.g. type IX and XII

Regulate organisation of collagen fibrils

26
Q

What is the basement membrane?

A

Aka. basal laminae
They are flexible, thin mats of ECM underlying epithelial sheets and tubes
They’re highly specialised ECMs containing a distinct repertoire of collagens, glycoproteins and proteoglycans

27
Q

Where are basement membranes found?

A

Surround muscle, peripheral nerve and fat cells and underlie most epithelia
In the kidney they form a key part of the filtration unit in the glomerular basement membrane (GBM)

28
Q

What is diabetic neuropathy?

A

An accumulation os ECM leading to highly thickened membrane

This results in restricted renal filtration and can lead to renal faliure

29
Q

What is Alport syndrome?

A

Mutation in collagen IV results in abnormally split and laminated GBM which is associated with progressive loss of kidney function and hearing loss

30
Q

Why are elastic fibres important?

A

Important for the elasticity of tissues such as skin, blood vessels and lungs
Often collagen and elastic fibres are interwoven to limit the extent of stretching

31
Q

What are elastic fibres made of?

A

A core made up of protein elastin and microfibrils which are rich in protein fibrillin

32
Q

What is the importance of fibrillin?

A

Integrity of elastin fibres depends on microfibrils containing protein fibrillin

33
Q

What is Marfan’s syndrome?

A

Associated with mutations in protein fibrillin-1
Has diverse manifestations involving primarily the skeletal, ocular and cardiovascular system
Individuals can be predisposed to aortic ruptures

34
Q

What is the structure of elastin?

A

Elastin consists of 2 types of segments that alternate along polypeptide chain:

  • hydrophobic regions
  • alpha-helical regions rich in lysine and alanine

Many lysine side chains are covalently cross-linked

35
Q

What is the modular architecture of ECM proteins?

A

Most ECM proteins are large and have a modular architecture:
compromised of characteristic protein domains of 50-200 amino acids
Multi-functionality of ECM proteins is a result of their modular structure

36
Q

What are laminins?

A

Multi-adhesive glycoproteins which can interact with a variety of cell surface receptors including integrins and dystroglycans
They can self-associate as part of the basement membrane but all interact with other matrix components e.g. type IV collagen, nidogen and proteoglycans

37
Q

How are laminins structured?

A

They’re heterotrimeric proteins made up of an alpha chain, beta chain and gamma chain which form cross shaped molecules

They’re very large proteins each having a molecular weight of 160-400 kDa

38
Q

What is fibronectin?

A

Multi-adhesive glycoproteins made up of a large multi-domain molecule linked by disulphide bonds
They’re a family of closely related glycoproteins of the ECM which are also found in bodily fluids

39
Q

What forms can fibronectin exist in?

A

Insoluble fibrillar matrix

Soluble plasma protein

40
Q

How are different fibronectins made?

A

They’re derived from a single gene with alternate splicing of mRNAs giving rise to different types

41
Q

What is the function of fibronectin?

A

Can interact with cell surface receptors and other matrix molecules
Play important roles in cell adhesion regulation and migration in a variety of processes, notably embryogenesis and tissue repair
Also important for wound healing, helping to promote blood clotting

42
Q

How do fibronectins link to actin cytoskeleton?

A

Fibronectins form a mechanical continuum with actin cytoskeleton of many cell types
Integrin receptors at cell surface provide linkage between matrix and cytoskeleton

43
Q

What are proteoglycans?

A

Core proteins which are covalently attached to one or more glycosmainoglycan (GAG) chains

44
Q

What are GAG chains made of?

A

Repeating disaccharide units with one of the two sugars being an amino sugar
Many GAGs are sulphated or carboxylated and carry a high negative charge as a result
This attracts a cloud of cations including Na+ resulting in large amounts of water being sucked into the ECM

45
Q

What type of proteoglycan families are there?

A

Basement membrane proteoglycans- e.g. perlecan
Aggregating proteoglycans e.g. aggrecans
Small leucine-rich proteoglycans e.g. decorin
Cell surface proteoglycans e.g. syndecans 1-4

46
Q

How is cartilage structured?

A

Has a matrix rich in collagen with large quantities of GAGs trapped within meshwork
Balance of swelling pressure is negated by tension in collagen fibres generating great tensile strength

47
Q

How many GAG chains are attached to proteoglycans?

A

Small proteoglycans have a single GAG chain attached

Some large proteoglycans carry up to 100 GAG chains

48
Q

What are the different groups of GAG chains?

A

Hyaluronan
Chondroitin sulfate and dermatan sulfate
Heparan sulfate
Kertan sulfate

49
Q

What is hyaluronan?

A

Aka. hyaluronic acid
Found in ECM of soft connective tissue
Distinct from other GAGs as its simply a carbohydrate chain without a core protein
Its unsulfated and made up of repeating disaccharides which can number up to 25000 sugars

50
Q

What is aggrecan?

A

A major constituent of cartilage ECM
Has highly sulphated GAGs which increases their negative charge
has a large number of negatively charged carboxyl groups
Multiple negative charges attract cations such as Na+ that are osmotically active
This leads to large quantities of water being retained

51
Q

What is osteoarthritis?

A

An erosive disease resulting in excessive ECM degredation

Cushioning properties of cartilage over end of bones is lost

52
Q

What is the effect of age on aggrecan?

A

With increasing age aggrecan is cleaved by aggrecanases and metalloproteinases
This leads to loss of aggrecan fragments to synovial fluid

53
Q

What are fibrotic diseases?

A

They arise as a result of excessive production of fibrous connective tissue
e.g. liver cirrhosis, fibrotic lung

POM (48 decks)

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