Lecture 6- Extracellular Matrix II Flashcards
Describe the general properties of ECM proteins
- LARGE
- MODULAR structure: made of protein domains –> MULIFUNCTIONAL
- MULT- ADHESIVE- bind matrix components and cell-surface receptors
What are laminins?
Basement membrane glycoproteins
Descibe the structure of laminins
- made of three chains: alpha, beta, gamma which form a cross-shape molecule
- Very Large
- Multi-adhesive
- Interact with surface receptors e.g. integrins, dystroglycan
- Can self-associate (in BM matrix) or associate with collagens and proteoglycans
Mutations in laminin can cause which disorders?
- Muscular dystrophy
- epidermolysis bullosa
Draw and label a molecule of laminin
1) Globular ends on alpha chain
2) Coiled-coil Domain
3) Self- assembly region- binds to other laminins
4) Integrin binding at tips of alpha chains and perlecan at bottom
What causes congenital muscular dystrophy? Describe some of its features
- absence of a2 in laminin 2
- symptoms visible from birth
- Hypotonia (decreased muscle tension)
- Generalised weakness
- deformities of the joints
What is fibronectin?
- connective tissue glycoprotein
Which two forms can fibronectin exist as?
- insoluble fibrillar matrix
- soluble plasma protein
- both derived from the same gene
Describe its molecular structure and some of its features
- Multi- adhesive
- Large multi domain molecule
- Interacts with cell surface receptors and other matrix molecules
- forms a dimer linked by sulphide bridges
State three of the roles of fibronectin
1) Cell adhesion and migration in embryogenesis and tissue repair
2) Wound healing, promotes blood clotting
3) Forms mechanical continuum with actin cytoskeleton
How does fibronectin link to the actin cytoskeleton?
Fibronectin — integrin — Actin
Integris integrate the extracellular and intracellular environments
Briefly online the structure of proteoglycans
- Core protein covalently bonded to one or more glycosaminoglycan chains
Describe the structure of GAGs
- GAGs = long, unbranched sugars made of repeating disaccharides
- one sugar is always an amino sugar
- may be sulphated or carboxylated
- Highle -vely charged
- occupy huge volume relative to mass –> hydrated gel resistant to compression
What are the 4 main groups of GAG chains and what do they depend on?
- Hyaluronan
- Chondroitin sulfate and dermatan sulfate
- Heparin sulfate
- Keratan sulfate
– depends on sugar types
Give three examples of proteoglycans and their associate GAG chain
- Decorin: DS
- Syndecan: HS
- Aggrecan: KS and CS
- Describe the structure of Hyaluronan
- Where is Hyaluronan synthesised?
- Simple carbohydrate chain with no core protein (not a proteoglycan)
- insulated
- single long chain
- Synthesised at cell surface, not ER/ Golgi
How are GAG chains and core proteins linked?
By a link tetrasaccharide
What are the monomers of Dermatan sulphate and Chondroitin sulphate?
Dermatan: Iduronic acid and N-acetylgalactosamine-4-sulfate
Chondroitin: Glucuronic acid and N-acetylgalactosamine-4-sulfate
Describe the structure of decorin and its function
- small proteoglycan
- binds to collagen fibers
- essential for fibre formation
- No decorin= weak collagen fibres = fragile skin
What is the most abundant type of cartilage and where is it found?
Hyaline cartilage
- nose, larynx, trachea, bronchi, ventral end of ribs, articular end of long bones
What is hyaline cartilage mostly made of and what is its function?
- aggrecans (which form aggregates with hyaluronans)
- cushion ends of long bones
Draw and annotate a molecule of aggrecan
1) Chondroitin S. attachment region
2) Keratan s. attachment region below this
3) Hyaluronan binding region below
4) Attached to Hyaluronan
5) Link protein next to this
Describe the GAGs associated with aggrecan and how they contribute to aggrecans properties
- Highly sulfated and also carboxylated
- Multiple negative charges from these attract cations e.g. Na+ which are osmotically active
- Retains large amounts of water
- When compressed water is given up, but reabsorbed when load is removed
- -> good for cartilage
What is osteoarthritis?
- Excessive loss of ECM
- cushioning properties of cartilage over long bones lost
- Leads to rubbing of bones and joint stiffness
- Cleavage of aggrecan by aggrecanase and metalloproteinase
- Aggrecan fragments –> synovial fluid
STRONG GENETIC COMPONENT
What are fibrotic disorders?
- Excessive production of fibrous connective tissue (mainly collagen)
- normal cells replaced by stif collagen matrix
USUALLY NON-GENETIC
