6 Extracellular Matrix Biology II Flashcards

1
Q

*Q: What is the size of most ECM proteins? What’s their architecture? Function? Adhesion?

A

A: Most ECM proteins are very LARGE

They have MODULAR architecture - they are composed of protein domains of 50-200 amino acid residues (each of the units in the diagram is a protein molecule)

multifunctionality of ECM proteins is a result of their modular structure (different domains give different functions)

many large modular proteins are multi-adhesive, binding various matrix components and cell surface receptors

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2
Q

*Q: Draw a diagram for perlecan. What is it?

A

A: basement membrane proteoglycan

sugar chains

\ /
o»[]o0o0[][][][][][]<><><><>

immunoglobulin-like (IG) domain

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3
Q

*Q: What are laminins? Size? Where are they found? What do they interact with? Adhesion?

A

A: - ubiquitous basement membrane glycoproteins (in ALL basement membranes)

  • very large
  • Interact with cell surface receptors // Can self-associate as part of the basement membrane matrix and can interact with other ECM components
  • Multi-adhesive
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4
Q

*Q: What are laminins derived from? Mutations?

A

A: Derived from several genes

Mutations associated with inherited disease e.g. muscular dystrophy and epidermolysis bullosa.

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5
Q

*Q: Draw a diagram for a laminin molecule and label.

A

A: Contains of 3 chains = Forms a CROSS-SHAPED MOLECULE (on its side)

Different regions on the laminin have different binding capacities
.                  NH2
 .                    |
 .                   2
 .                    |
H2N-----1-----------------------------4----------------------------5
 .                    |
 .                   3
 .                    |
 .                 NH2
  1. alpha chain (at end, allows binding to integrin)
  2. beta chain (at end allows self-assembly)
  3. gamma chain (at end allows self-assembly)
    - > just above 3 = binding zone for nidogen
  4. coiled-coil domain (three chains are wrapped around each other)
  5. carboxylic end (allows binding to integrins, dystroglycan, perlecan)

At the N terminus all the chains have Globular Regions

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6
Q

*Q: What causes congenital muscular dystrophy? When are symptoms evident from? Symptoms are?

A

A: Absence of alpha 2 in laminin 2 caused by mutation

birth

  • Hypotonia: abnormally decreased muscle tension
  • general weakness
  • Deformities of the joints
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7
Q

*Q: What are fibronectins? Where is it not found? Can exist as? (2) Interactions?

A

A: family of closely related glycoproteins of ECM and body fluids // major connective tissue glycoprotein

NOT found in basal membranes

Can exist as insoluble fibrillar matrix or soluble plasma protein

LARGE - capable of interacting with cell surface receptors and other matrix molecules eg collagen // Multi-adhesive

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8
Q

Q: Why are fibronectins important?

A

A: regulating cell adhesion and migration in embryogenesis and tissue repair

wound healing (promotes blood clotting)

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9
Q

Q: What are fibronectins derived from? Mutations?

A

A: Only derived from ONE GENE - different forms of fibronectin come from different types of mRNA splicing.

NO KNOWN MUTATIONS IN HUMANS - suggests that it is essential for life (wouldn’t be viable if mutation present)

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10
Q

Q: Draw a diagram for a fibronectin molecule and label.

A

A: -lots of different domains= multiadhesive
-dimer connected by disulphide bridge-> V shape

N N
\ /
1 1
\ /
\ /
2 2
\ /
3 3
\ /
[] []
\ /
|-S-S-|
|-S-S-|
C C

  1. collagen binding
  2. integrin binding (includes RGD sequence)
  3. heparin binding
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11
Q

Q: How are fibronectin and actin related? Draw diagram to represent.

A

A: Forms a mechanical continuum with the actin cytoskeleton (same orientation)

extracellular fibronectin fibrils (indirectly linked to inside of cells via… intracellular actin stress fibres

integrin receptors at the cell surface provide the linkage between the matrix and cytoskeleton

collagen
     V (fibronectin)
integrin
plasma membrane
other side of integrin
adapter protein
actin filament
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12
Q

Q: How does fibronectin bind to integrin?

A

A: via RGD molecules on fibronectin

Integrin binds to the RGD sequence which is on the cell binding site

Integrins recognise the RGD motif

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13
Q

Q: Describe the RGD sequence.

A

A: loop of the integrin binding region

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14
Q

*Q: What are proteoglycans? Structure? Size is determined by? Key Property?

A

A: type of glycoprotein

  • CORE PROTEIN
  • one or more GLYCOSAMINOGLYCAN (GAG) CHAINS are covalently attached
  • Small proteoglycans have one GAG chain where as large ones can carry around 100 GAG chains (GAGs occupy a large volume relative to their mass)

resistant to compression

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15
Q

Q: What is the structure of GAG chains? Charge? Property?

A

A: -GAG chains are long, unbranched sugars consisting of a REPEATING DISACCHARIDE
-One of the two sugars in the repeating disaccharide is always an amino sugar

  • Highly Negatively Charged - many GAGs are sulfated or carboxylated
  • GAGs form hydrated gels which can be very resistant to compression
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16
Q

*Q: What are the families that proteoglycans are categorised into based on? What are the 4 families?

A

A: structural and functional characteristics

  • Basement Membrane e.g. perlecan
  • Aggregating (interact with hyaluron) e.g. aggrecan in cartilage
  • Small Leucine-Rich e.g. decorin
  • Cell Surface e.g. syndecans 1-4 (not part of ECM)
17
Q

Q: Name 4 main groups of GAG chains.

A

A: -Hyaluron

  • Chondroitin Sulfate/Dermatan Sulfate
  • Heparan Sulfate
  • Keratan Sulfate
18
Q

*Q: Give 3 examples of GAG chains on proteoglycans.

A
A: decorin: single GAG chain
     /
   /
  n
C C
syndecan: 3
         N
   ------|
   ------|------
          |
 PM==|=== (transmembrane part)
         \ / 
             C (cystolic region)

aggrecan: 100s
||||| ||||||||||||||||||||||||||||||||
N———————————–C
||||| ||||||||||||||||||||||||||||||||

19
Q

Q: What connects GAG chains and the core protein?

A

A: LINK TETRASACCHARIDE

xylose-galactose-galactose-glucuronic acid

20
Q

Q: What is hyaluron also called? Why is it unique? Where is it synthesised? Size?

A

A: -hyaluronic acid.

  • NO CORE PROTEIN - it only has a carbohydrate chain (not proteoglycan)
  • Synthesised in the cell surface - NOT in the ER/Golgi

-Hyaluron is a HUGE molecule which occupies about the same volume as a bacterium.

21
Q

Q: What’s the structure of hyaluron? (3)

A

A: -Unsulfated

  • contains lots of carboxyl groups
  • A single long chain has up to 25,000 repeat disaccharides
22
Q

*Q: What’s the structure of Dermatan Sulfate?

A

A: glycosaminoglycan /GAG

C=iduronic acid, S= N-acetylgalactosamine-4-sulfate

carboxyl and sulphate repeating disaccharide (makes it negatively charged)

23
Q

*Q: What’s the structure of Chondroitin Sulfate?

A

A: glycosaminoglycan /GAG

C=glucuronic acid, S= N-acetylgalactosamine-4-sulfate

carboxyl and sulphate repeating disaccharide (makes it negatively charged)

24
Q

Q: What is decorin? Binds to? Mice that can’t produce have? Regulates?

A

A: -Small proteoglycan

  • Binds to collagen fibres
  • Mice who cannot make decorin have fragile skin and reduced tensile strength (collagen hasn’t formed correctly)
  • Regulates collagen fibre size and arrangement (essential for fibre formation)
25
Q

Q: What’s the structure of the cartilage matrix?

A

A: filamentous network of proteoglycans with embedded collagen fibres (type II)

26
Q

Q: Describe hyaline cartilage abundance? What’s it rich in? Where’s it found? (6) Function? Property?

A

A: -Most abundant type of cartilage

  • aggrecan
  • nose, larynx, trachea, bronchi, ventral ends of ribs, articular end of long bones

cushion ends of long bones

27
Q

Q: What is aggrecan a major constituent of? Structure? Association with hyaluronan?

A

A: cartilage matrix

………….||1| ||||||||||2||||||||||||||||||||||
N-3———————————-C
………….||1| ||||||||||2||||||||||||||||||||||

  1. keratan sulfate attachment region
  2. chondroitin sulfate attachment region
  3. hyaluronan binding region

The core protein of aggrecan is linked to hyaluronan at N end -> makes a complex and hyaluronan has a link protein which makes the structure very LARGE

28
Q

Q: Does aggrecan aggregate? Overall structure?

A

A: yes- the complex of aggrecan, hyaluronan and the link protein

29
Q

Q: How does the structure of aggrecan aid cartilage function?

A

A: Aggrecan and Cartilage Function

The GAGs of aggrecan are highly sulfated and there are many carboxyl groups - this makes it HIGHLY NEGATIVELY CHARGED

The high negative charge attracts cations that are osmotically active (e.g. Sodium)

So a large amount of WATER is retained by this highly negatively charged environment (hydrated)

It forms a gel - if you put pressure on the structure(under compressive load), the water gets squeezed out and if the compressive load is removed - the water returns.

This is how aggrecan can withstand compressive forces.

30
Q

Q: What is osteoarthritis? Common? Mostly affects?

A

A: -erosive disease caused by excessive loss of ECM= cushioning properties of cartilage over the end of long bones are lost

  • most common human disease in britain
  • strong genetic component by genetics are complex
  • mostly affects elderly
31
Q

Q: What does osteoarthritis affect? Process?

A

A: affects joints

  • with age: cleavage of aggrecan by aggrecanase and metalloproteinase
  • loss of aggrecan fragments to synovial fluid

joints lose cartilage -> bones rub -> painful + get inflammation -> joints=swollen + can get bony growths called heberden’s nodes

32
Q

Q: What causes fibrotic disorders? Result? 2 examples?

A

A: excessive production of fibrous connective tissue (mostly collagen)- normal cells in tissue are replaced with stiff collagen matrix = cells in organ can no longer function correctly

disorder where organ can have a lot of scar tissue as a result

  • liver cirrhosis
  • ling fibrosis