4. Extracellular Matrix II Flashcards
List the 3 major components of the ECM
Collagens
Glycoproteins
Proteoglycans
What do ECM molecules consist of?
Large, modular proteins
50-200 AAs
Multifunctional and multi-adhesive
Give 2 examples of multi-adhesive glycoproteins.
Fibronectin
Laminin
Describe the structure of Laminin.
Cross shaped molecule consisting of an alpha, beta and gamma chain
Very large (160-400 kDa)
The N terminus of all the chains there are globular regions
There is a coiled-coil region in which the 3 chains are wrapped around each other
What can laminin interact with?
Can self-associate as part of the BM Can interact with: Cell surface receptors e.g. integrins Type IV collagen Proteoglycans
What causes congenital muscular dystrophy?
Absence of alpha 2 chain in laminin 2
Characteristics of congenital muscular dystrophy
Symptoms evident from birth
Hypotonia (abnormally decreased muscle tension)
Generalised weakness
Deformities of the joints
Describe the structure of fibronectins
Large multi-domain molecule: dimer (500 kDa) joined by disulphide bonds
Insoluble fibrillar matrix or soluble plasma protein
Derived from 1 gene (alternate splicing at mRNA level)
What do fibronectins interact with?
Cell surface receptors and other matrix molecules
What important roles are fibronectins involved in?
Regulating cell adhesion and migration in embryogenesis and tissue repair
Wound healing
What do fibronectins form a mechanical continuum with and how?
Actin cytoskeleton of many cell types
Integrin receptors
Why is fibronectin considered essential for life?
There are no known mutations of fibronectin in humans
What part of fibronectin do integrins bind to?
RGD motif
Describe the general structure of proteoglycans.
Consists of a core protein with 1 or more glycosaminoglycan (GAG) chains covalently attached
What are glycosaminoglycans?
Long, unbranched sugars consisting of repeating disaccharides
Occupy huge volume relative to their mass
What is a characteristic feature of GAG chains?
Can form hydrated gels which are resistant to compression
Name 4 proteoglycan families
BM: e.g. perlecan
Aggregating: e.g. Aggrecan
Small leucine-rich: e.g. decorin
Cell surface: e.g. syndecans 1-4
Variability in size of proteoglycans
Small: Have single GAG attached
Large: Carry 100 GAG chains
What are the 4 families of GAG chains?
Hyaluronan
Heparan Sulfate
Chondroitin Sulfate and Dermatan sulphate
Keratan sulfate
What is unique about hyaluronan structure?
Doesn’t have a core protein (simply carbohydrate chain)
Synthesised at the cell surface rather than by the ER
Un-sulphated
Single long chain up to 25,000 repeating disaccharides
How are GAG chains linked to the core protein?
Connected via a link tetrasaccharide
What is Decorin?
Small proteoglycan
What does Decorin do?
Binds to collagen fibres, essential for fibre formation
What is the most abundant type of cartilage?
Hyaline
What does hyaline cartilage consist of?
Aggrecan aggregates
Aggrecan (GAG chains = keratan sulphate and chondroitin sulphate) associated with hyaluronan and a link protein
Where is hyaline found?
nose larynx trachea bronchi ventral ends of ribs articular ends of long bones
What is the function of hyaline?
Cushion ends of long bones
Describe how hyaline cartilage resists compressive force.
GAG chains in aggrecan are heavily sulphated and carboxylated so it is very negatively charged.
This means it can attract osmotically active cations (Na+ and Ca2+), which attracts water forming a gel like substance
Under compressive load, water is squeezed out and returns when the compressive force is removed
Therefore good for resisting compressive forces
What causes osteoarthritis?
Loss of extracellular matrix
Over time aggrecan is cleaved and fragments are lost to synovial fluid
What is the result of excess ECM degradation in osteoarthritis?
Cushioning properties of cartilage over ends of bones are lost
What happens in fibrotic disorders?
Excess production and deposition of fibrous connective tissue
