2.10 ECM Flashcards
1
Q
What is the extra cellular matrix?
A
A complex network of proteins and carbohydrates that fill the spaces between cells
2
Q
What type of components does the ECM consist of?
A
Fibrillar and non-fibrillar components
3
Q
What does fibrillar mean?
A
Makes fibre
4
Q
What are the two types of roles that the ECM plays in the cell?
A
An architectural role (influencing mechanical stability) and an instructional role (influences cell behaviour)
5
Q
What three things is the ECM essential for?
A
Development, tissue function and organogenesis
6
Q
What are three key functions of the ECM?
A
- Physical support
- Determines mechanical and physicochemical properties of tissue
- Influences the growth, adhesion and differentiation status of the cells and tissues
7
Q
What type of tissue is particularly rich in extra cellular matrix?
A
Connective tissue
8
Q
What are the three main components of the extra cellular matrix?
A
Collagens
Multi-adhesive glycoproteins
Proteoglycans
9
Q
What is found in the basement membrane?
A
Type IV collagen (non-fibrillar)
Laminins
Perlecan
10
Q
How can connective tissues have such varied properties?
A
The different types and arrangements of collagen, with the presence of different ECM components
11
Q
What properties do connective tissues in tendon and skin have?
A
Tough and flexible
12
Q
What properties do connective tissues in bone have?
A
Hard and dense
13
Q
What properties do connective tissues in the cartilage have?
A
Resilient and shock absorbing
14
Q
What cell produces collagen?
A
Fibroblasts
15
Q
What is connective tissue made up of?
A
Extracellular matrix and component cells
16
Q
What are 5 proteoglycans? (PADS V)
A
Perlecan
Aggrecan
Decorin
Syndecans 1-4
Versican
17
Q
What type of protein is collagen?
A
Fibrous
18
Q
How many different collagen types exist in humans?
A
28
19
Q
What structure does collagen form?
A
Triple helix
20
Q
What is meant by a homotrimer?
A
When there is only one chain type
21
Q
Which types of collagen are homotrimers?
A
Type II and III
22
Q
What are the compositions of type II and type III collagen?
A
Both have 1 chain type
23
Q
What is meant by a heterotrimer?
A
When the chains arise from 2 genes
24
Q
What type of collagen is a heterotrimer?
A
Type I Collagen
25
What is the composition of type I collagen?
26
What are commonly the amino acids x and y in the glycine-x-y-repeat?
X = proline
Y = hydroxyproline
27
Which amino acid occupies every third position in collagen proteins?
Glycine
28
Why is glycine heavily involved in the structure of collagen?
Glycine is the only amino acid which is small enough to occupy the interior of the triple helix
This gives collagen a stiff triple helix structure
29
What provides tensile strength and stability in collagen?
Intermolecular and intramolecular cross links
30
When does cross linking in collagen take place?
Only after the collagen has been secreted
31
What is an essential post-translational modification which contributes to interchain hydrogen bond formation?
The hydroxylation of proline and lysine
32
What enzymes are needed for the hydroxylation of proline and lysine?
Prolyl hydroxylase and lysyl hydroxylase
33
What do Prolyl hydroxylase and Lysyl hydroxylase requires as a co-factor?
Fe2+ and vitamin C
34
What happens to collagen when you have vitamin C deficiency? What is this called?
The collagen is underhydroxylated thus affecting tissue stability
This is called **scurvy**
35
When does the cross linking of collagen occur?
After the fibril formation
36
What are the steps to collagen synthesis in fibroblasts?
37
What collagens are non-fibrillar (fibril-associated)?
Type IV, IX, X
38
What do fibril associated (non-fibrillar) collagens do?
They regulate the organisation of fibrillar collagens in tissues
39
What are the symptoms and cause of Ehlers-Danlos syndrome?
Stretchy skin and loose joints (joint hypermobility)
Due to mutations affecting collagen production in connective tissue
40
How is the tensile strength of collagen established?
The fibres are held in parallel bundles which resist the tensile force in one direction
41
What are collagen alpha chains synthesized from?
Longer precursors called pro-alpha chains
42
What is cleaved from procollagen to make collagen in the case of **fibrillar** collagens?
N-terminal propetide and C-terminal propeptide
43
Where is type IV collagen found?
In all basement membranes
44
What type of network does type IV collagen form?
A sheet-like network
45
What happens to the N and C terminus in type IV collagen?
It remains intact as type IV is **non-fibrillar**
46
What does uncleaved N and C termini allow type IV collagen to do?
Interact with other collagen molecules to form a network of collagen, acting as a **basement membrane**
47
What is another name for basement membranes?
Basal lamina
48
What is the basement membrane?
A thin, flexible mat of extra-cellular matrix which the epithelial cell sheet sits on top of
49
What structures are surrounded by basement membrane?
Muscle, peripheral nerve and fat cells
50
What do basement membranes form a part of the kidney?
They form a key part of the filtration unit as the glomerular basement membrane
51
What is diabetes nephropathy?
Disorder where there is an accumulation of ECM leading to highly thickened basement membrane
This results in **less renal filtration** and can cause renal failure
52
What is Alport Syndrome?
Where mutations in collage IV result in an **abnormally laminated glomerular basement membrane**
This is associated with progressive **loss of kidney function** and **hearing loss**
53
What helps to limit the extent of elastic fibres stretching?
The elastic fibres are interwoven with collagen
54
What do elastic fibres consist of?
A core made up of **elastin** protein, surrounded by **microfibrils** which are rich in the protein fibrillin
55
What amino acid side chains are covalently cross linked in elastin?
Lysine
56
Describe the structure of elastin fibres
Elastin consists of two types of segments that alternate along the polypeptide chain:
**Hydrophobic** regions and an **alpha-helical** region that is rich in lysine and alanine – many of these lysin side chains are covalently crosslinked
57
Where is fibrillin found?
In the microfibrils which surround the elastin core
58
Mutations in fibrillin-1 are associated with what syndrome?
Marfans Syndrome
59
What are patients with Marfans syndrome pre-disposed to and what symptoms do they have?
Predisposed to aortic ruptures
Long spiderlike fingers and long slender limbs
60
How are ECM proteins able to multi-function?
They have a modular structure
61
What is meant by multi-adhesive modular proteins?
The proteins can bind various matrix components and cell-surface receptors
62
What is the shape of the laminin molecule?
A cross shape due to the presence of three chains - alpha, beta and gamma
63
Are laminins large or small proteins?
Large
64
Which surface cell receptors can laminins interact with?
Integrins and dystroglycans
65
What structure can laminins self associate as part of?
Basement membrane matrix
66
What other matrix components can laminins interact with?
Type IV collagen, nidogen, proteoglycans
67
What mutation of laminin results in congenital muscular dystrophy?
Absence of the alpha-2 chain in laminin-2
68
What are some symptoms of congenital muscular dystrophy?
Hypotonia (decreased muscle tension)
Generalised muscle weakness
Deformities of the joints
69
What are the two forms which fibronectins can exist as?
Insoluble fibrillar matrix or soluble plasma proteins
70
How are different forms of fibronectins formed?
Alternate splicing of mRNAs
71
What do fibronectins do?
Regulate cell surface adhesion
Regulate migration in a variety of processes, notably embryogenesis
Tissue repair
72
Explain the multi-domain structure of fibronectin
Several domains are linked by disulphide bonds
Several collagen and cell binding sites are present
73
How is fibronectin involved in the binding of collagen fiber to actin filament?
Fibronectin binds a **collagen fibre** and the **integrin receptor** on the other side, providing linkage between the ECM and cytoskeleton
**Adaptor protein** binds to the **other end** of the **integrin** receptor, and an **actin filament** binds to the adaptor protein
74
What is a proteoglycan?
Core proteins which are covalently bonded to one or more glycosaminoglycan chains
75
What proteoglycan is considered small and leucine rich?
Decorin
76
What is the name of a cell surface proteoglycan?
Syndecans
77
What is a GAG chain?
Glycosaminoglycan chain
78
What makes up a GAG chain?
Repeating disaccharide units with one of the two sugars being an amino sugar
79
What is an amino sugar?
A sugar in which one of the hydroxyl group is replaced with a amine group
80
What has to happen to the GAG chain in order for it to carry a high negative charge?
Has to be sulfated or carboxylated
81
What effect does the high negative charge of the GAG chain result in?
It attracts **clouds of cations**, including Na+, which therefore **pulls water into the ECM** through osmosis
82
Why does cartilage have a high tensile strength?
Cartliage has ECM rich in **collagen** and **glycosaminoglycan chains** trapped in mesh
Thus the balance of swelling pressure is negated by the tension in the collagen fibres
83
What are the four groups of GAG chains?
Hyaluronan
Chondroitin sulfate
Heparan sulfate
Keratan sulfate
84
How is hyaluronan produced?
It is spun out directly from an enzyme embedded in the plasma membrane
85
How is hyaluronan distinct from other GAG chains?
It is simply a carbohydrate chain without a core protein and is unsulfated
86
Why can hyaluranan chains occupy large volumes?
Because it can undergo a very **high degree of polymerisation**, which creates very large molecules
87
What is the role of hyaluronan in the synovial fluid of joints?
Protects the cartilaginous surfaces from damage
88
Where else is hyaluornan found apart from in the synovial fluid of joints?
Vitreous humour of the eye
89
What is a major constituent of the cartilage ECM?
Aggrecan
90
Aggrecan is highly sulphated. What effect does this have?
Increases their **negative charge** which **attracts cations** that are osmotically active - leads to large amounts of water being retained by the negatively charged environment
91
what is osteoarthiritis?
an erosive disease resulting in excessive ECM degradation
92
What is lost with osteoarthiritis?
The cushioning properties of cartilage over the end of bones
93
What leads to a loss of aggrecan fragments to the synovial fluid?
The cleavage of aggrecan by aggrecanases and metalloproteinases - this increases with age
94
How do fibrotic diseases arise?
They are as a result of excessive production of fibrous connective tissue
95
How is aggrecan perfectly suited to resist compressive forces in cartilage matrix?
Under compressive load, water is given up but is regained once the load is reduced
