1.1 POM Cells > Extracellular `Matrix > Flashcards

Extracellular `Matrix Flashcards

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1
Q

What are the macromolecules making up ECM?

A
  1. Protein
  2. Carbohydrates
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2
Q

What is ECM?

A

Extracellular matrix

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3
Q

What are the 4 functions of ECM?

A
  1. Physical support
  2. Tissue properties
  3. Influences cell growth/adhesion/differentiation
  4. Organogenesis
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4
Q

Which cells deposit ECM?

A

Fibroblasts

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5
Q

What are the 3 components of ECM?

A
  1. Collagens
  2. Glycoproteins (multi-adhesive)
  3. Proteoglycans
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6
Q

What are the 4 types of collagens in connective tissue?

A
  1. I
  2. II
  3. III
  4. IV —> basement membrane
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7
Q

What are the 3 types of multi-adhesive glycoproteins in connective tissue?

A
  1. Fibronectin
  2. Fibrinogen
  3. Laminins —> basement membrane
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8
Q

What are the 4 types of proteoglycans in connective tissue?

A
  1. Aggrecan
  2. Versican
  3. Decorin
  4. Perlecan —> basement membrane
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9
Q

What are the 3 components of the basement membrane?

A
  1. Type IV collagen
  2. Laminins
  3. Perlecan
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10
Q

How do matrix components interact with cells?

A

Bind to integrins on cell surface (receptors)

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11
Q

What are integrins?

A

Transmembrane cell adhesion receptors —> mediating cell-to-cell and cell-ECM interactions

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12
Q

What are the 2 properties of tendon and skin tissue?

A
  1. Tough
  2. Flexible
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13
Q

What are the 2 properties of bone tissue?

A
  1. Hard
  2. Dense
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14
Q

What are the 2 properties of cartiledge tissue?

A
  1. Resilient
  2. Shock-absorbing
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15
Q

Are connective tissue properties consistent around the body?

A

No —> vary depending on tissue function

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16
Q

How does connective tissue vary its properties?

A
  1. Different ECM components (eg. collagen types)
  2. Different arrangements of collagen
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17
Q

How do ECM abnormalities arise? (4)

A
  1. Mutations affecting ECM proteins
  2. Mutations affecting ECM catabolism
  3. Excess ECM
  4. Loss of ECM
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18
Q

What are 5 examples of disorders resulting from mutated ECM proteins?

A
  1. Osteogenesis imperfecta (Brittle bones) - collagen I
  2. Marfan’s syndrome - fibrillin I
  3. Alport’s syndrome - collagen IV
  4. Epidermolysis Bullosa - laminin 5
  5. Muscular dystrophy (congenital) - laminin 2
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19
Q

What is an example of a disorder resulting from ECM catabolism issues?

A

Hurler’s syndrome - L-α-iduronidase

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20
Q

What are 3 examples of disorders resulting from excess ECM deposition? (fibrosis)

A
  1. Liver cirrhosis
  2. Diabetic nephropathy
  3. IPF (idiopathic pulmonary fibrosis)
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21
Q

What does excess ECM deposition lead to?

A

Fibrosis

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22
Q

What is an example of a disorder resulting from loss of ECM?

A

Osteoarthritis

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23
Q

What are collagens?

A

Family of fibrous proteins

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24
Q

Which organs are collagens essential for?

A
  1. Bones
  2. Tendons
  3. Skin
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25
What is the most abundant protein in mammals?
Collagen
26
What proportion of the protein mass of mammals is collagens?
25%
27
What is the arrangement of collagen fibrils in skin/bone/cornea and why?
Successive layers at right angles - High tensile force
28
How many types of collagens exist in humans?
28
29
How many genes encode the collagens in humans?
42
30
What is the quaternary structure of a collagen molecule?
3 α-chains form triple helix
31
What is the quaternary structure of type I collagen?
2 α1-chains and 1 α2-chain
32
What are the 3 chains making up type I collagen molecules?
2 α1 + 1α2
33
What is the tertiary structure of type II and III collagen?
3 α1-chains
34
What is the primary structure of α collagen chains?
Repeated gly-x-y - Usually glycine-proline-hydroxyproline
35
Why is fibrillar collagen described as a left-hand helix?
3 α-chains coils left (anti-clockwise)
36
Why must every 3rd amino acid in a collagen molecule be glycine?
Small enough to occupy interior of coil
37
What are the 4 stages of collagen fibre synthesis?
1. α-chain 2. 3 α-chains in triple helix 3. Fibril 4. Fibre
38
What is the difference between procollagen and collagen?
Procollagen has non-collagenous N- and C-termini
39
How is procollagen turned into collagen?
N- and C-termini removed - Post-secretion in fibrillar collagens - Pre-secretion in non-fibrillar
40
What forms between collagen fibres and why?
Cross-links (covalent) - increases strength and stability
41
What are the 7 steps of collagen fibre biosynthesis?
ER/Golgi 1. Pro-α chain synthesised 2. Hydroxylation of prolines and lysines (post-translational modifications) 3. Glycosylation of hydroxylysines 4. 3 pro-α chains assemble ---> triple helix ---> procollagen 5. Procollagen to cytoplasm via secretory vesicle and exocytosis ECM 6. Propeptides cleaved ---> collagen 7. Fibril assembly 8. Fibre assembly
42
Where does collagen fibre biosynthesis occur? (2)
1. ER/Golgi ---> procollagen 2. ECM ---> collagen fibre
43
How do collagen cross-links change with age?
Number increases with age ---> joint stiffness
44
What do prolyl and lysyl hydroxylases require? (2)
1. Fe2+ 2. Vitamin C
45
Which enzymes are involved in post-translational modification of collagen?
Prolyl and lysyl hydroxylases
46
What type of bonding in collagen do hydroxylysine and hydroxyproline contribute to?
H-bonding
47
Which amino acids contribute to interchain H-bond formation in collagen?
1. Hydroxylysine 2. Hydroxyproline
48
When is collagen lysine and hydroxylysine modified? (2)
Post-translation in golgi/ER
49
What does vitamin C deficiency lead to and why?
Scurvy - vit C needed for hydroxylases ---> under-hydroxylated collagens ---> decreased tissue stability
50
What is EDS?
Ehlers-Danlos Syndrome - Group of inherited connective tissue disorders
51
What are the 2 symptoms of EDS?
1. Stretchy skin 2. Loose joints
52
When do mutations in collagen result is disorders? (3)
1. Change production 2. Change structure 3. Change processing
53
What are the 3 types of collagen?
1. Fibrillar (I, II, III) 2. Fibril-associated (IX, XII) 3. Network-forming (IV)
54
What is the function of fibril-associated collagens?
Regulate organisation of collagen fibrils
55
What are the 2 fibril-associated collagens?
1. IX 2. XII
56
Where is network-forming collagen found?
Basement membranes
57
What collagen is network-forming collagen?
IV
58
What category of collagen is type I, II and III?
Fibrillar
59
What category of collagen is type IV?
Network-forming
60
What category of collagen is type IX and XII?
Fibril-associated
61
What type of collagen is in basement membranes?
IV
62
What can be seen in a fibrotic lung?
Honeycombing (excess collagen)
63
What are basement membranes?
Membranes separating different tissue layers
64
What happens to the glomerular basement membrane in diabetics?
Fibrosis ---> thickened
65
Why can diabetes lead to renal failure?
Glomerular basement membrane fibrosis ---> inhibits renal filtration
66
What is the cause of Alport syndrome and why?
Mutation in collagen IV ---> split and laminated glomerular basement membrane
67
What are laminins?
Family of large, multidomain glycoproteins
68
What is the quaternary structure of laminins?
Coil of 1α, 1β and 1γ chain
69
What can the the N- and C-termini of α chains in laminins bind to?
- N ---> integrins - C ---> integrins, dystroglycan and perlecan
70
What can the the N-terminus of β and γ chains in laminins bind to?
Nidogen
71
Why do laminins have stability?
Heterotrimeric coil structure
72
What is the distinctive shape of laminins?
Cross
73
What is the cause of muscular dystrophy?
LAMA2 mutation ---> laminin-α2 deficiency (truncated protein)
74
What is a heterotrimer?
Complex consisting of 3 different sub-units - eg. Laminins
75
What does LAMA2 gene truncation cause and how?
Congenital muscular dystrophy - lamanin can't bind to integrin (α7β1) or α-dystroglycan ---> inhibits basement membrane assembly
76
What are the 2 symptoms of muscular dystrophy?
1. Muscle weakness 2. Muscle degeneration
77
Why do tissues have elasticity?
Elastic fibres
78
Where are elastic fibres found? (3)
1. Skin 2. Blood vessels 3. Lungs
79
What are elastic fibres made up of?
1. Elastin core 2. Surrounded by fibrillin-rich microfibrils
80
What is the arrangement of elastin?
Random coil
81
What are the 2 domains in elastin and how are they arranged?
- Hydrophobic and hydrophilic - Alternating
82
How does crosslinking occur in elastin?
Via lysine residues in the hydrophilic domains
83
What is the cause of Marfan's syndrome?
Fibrillin-1 mutations
84
Which 3 systems are primarily effected by Marfan's syndrome?
1. Skeletal 2. Ocular 3. Cardiovascular
85
Which blood vessel does Marfan's syndrome affect and how?
Aorta - Fragmentation - Disarray of elastic fibres
86
What is fibronectin?
Glycoprotein in ECM
87
What are the 5 functions of fibronectin?
1. Interact with cell surface receptors and ECM molecules 2. Regulate cell adhesion 3. Regulate tissue repair 4. Wound healing and blood clotting 5. Regulate migration in embryogenesis
88
What is the structure of fibronectin?
2 sub-units linked by di-sulfide bridge at C-terminus
89
What is the identifiable shape of fibronectin?
Omega symbol worm
90
What do fibronectins link in cells and how?
Cytoskeleton to ECM - Cell attachment sites to integrins on cell surface membrane ---> integrins bind to actin filaments inside the cell - N-terminus ends bind to collagen fibril in ECM
91
What are proteoglycans?
Core proteins with attached glycosaminoglycan chains (GAG)
92
What are GAG chains?
Glycosaminoglycan chains - Polymer of repeating disaccharides
93
What can affect the charge of proteoglycans and what does this do?
Sulfation and carboxylation - attract more water and cations
94
What are the 4 types GAG and where are they made?
1. Hyaluronan - membrane 2. Chondroitin/dermatan sulfate - ER/golgi 3. Heparan sulfate - ER/golgi 4. Keratan sulfate - ER/golgi
95
Where is the proteoglycan hyaluronan found?
High viscous tissues - eg. Fluid of eyes and joints
96
What is the key function of the proteoglycan hyaluronan?
Protect cartilaginous
97
What is the structure of hyaluronan?
- No core protein - Cluster of saccharide chains
98
Where is the proteoglycan aggrecan found and why?
Cartilage matrix - Resist compressive forces
99
How does the proteoglycan aggrecan resist compressive forces?
Lose water under compressive load ---> gain water when load is reduced
100
What is the leading cause of lower extremity disability in adults?
Osteoarthritis
101
What is osteoarthritis?
ECM degradation at bone ends
102
What is the cause of osteoarthritis?
Aggrecan cleaved by aggrecanases and metalloproteinases ---> cartilage at end of bones no longer cushioning
1.1 POM Cells
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