Flashcards in ECM Deck (20):
What are the four macromolecular components.
What is the ground substrate.
1. Structural proteins (collagen, elastin)
2. Glycosaminoglycans (GAG) they are sugars that bind water and resist compression (cause of negative charge)
3. Proteoglycans: proteins coupled with GAG
4. Adhesive glycoproteins (fibronectin and laminin)
Ground substrate includes water, ions and these macromolecular components. Include cells and it is connective tissue.
Describe the three layers that form the basal membrane.
1. Lamina lucida (electron poor region)
2. Lamina densa (type four collagen, perlecan-a proteoglycan)
3. Lamina reticularis - made by fibroblasts and contains type 3 collagen.
It is the most abundant protein in the body, it provides tensile strength and resists stretching.
It is a repeating sequence of glycine-N-N so a glycine at every third. This allows the H chain to fit inside the alpha helix allowing for triple helix formation.
Collagen has a distinct striation pattern due to selective electron addition.
How is collagen formed?
Collagon pro-alpha chain is made on free ribosomes. Then SRP brings it to the ER. IN the ER/Golgi compartment, the prolines and lysines are hydroxylated. These hydroxy groups form hydrogen bonds which stabilize the trimer. Hydrolase uses vitamin C as a cofactor of hydroxylase. (this is why scurvy causes your teeth to fall out because the turnover of collagen is too slow)
The extension peptides remain on as they are secreted
Once secreted they are a procollagen molecule and cleaving the propeptides forms a collagen molecule which can self assemble into a fibril with other molecules.
Glycine mutation or hydrolase mutation will disrupt this process.
What is type III collagen
Where are type 1 and 2 found?
Part of skin and blood vessels
Found in lamina reticularis.
It has more carbohydrate, thinner fibrils and more branches. It will stain uniquely with a silver stain.
Type 1 is found in bone
Type 2 is found in cartilage.
What is collagen type IX.
Unique in that extension peptides are generally retained.
it will decorate the outside of type II collagen of chondrocytes.
They are fibril associated collagen and not fibril producing.
if mutated then epiphyseal dysplasia occurs and arthritis occurs.
Describe Type IV collagen
They are network forming collagen of the lamina densa and is the major collagen of the basal lamina.
The extension peptides are not cleaved and the C and N termini interact.
Forms a chicken wire array
What are type VII and XVII collagen?
Type 7 is anchoring fibrils. Type VII interact via C terimini disulfide bonds.
They connect the type 4 lamina densa to the underlying connective tissue.
Type 17 is a transmembrane protein (found in hemidesmosomes) that connects the epithelium to the basement membrane and a mutation will cause blistering.
Elastin monomers are cross linked and like collagen is assembled extracellularly. They can be stretched and relaxed.
Elastic fibers are surrounded by microfibrils which are composed of fibrillin.
What is Marfan syndrome?
It is a fibrillin mutation. It causes the appearance of long appendages and a aorta that is prone to rupture (which has a high concentration of fibrillin and collagen)
It is thought that the lack of recoil provided by fibrillin leads to increased length of the appendages.
What is hyperextendable skin?
Hyperextendable skin: type III collagen
Altered elastin - if you pull it, the skin won't even retract.
Epidermolysis bullosa - mutation in type 7 anchoring fibirls and the BM and Epithelium peel apart.
What are glycosaminoglycans?
They are long sugar molecules, that have alternating acid and amino sugars.
They are negatively charged so they resist compression and bind a lot of water.
Most feature sulfates to add to the acidic monomer's negative charge and associate with proteins. However hyaluronic acid is non sulfated and no covalent protein binding.
Primarily found in the joints and eye
What is found in the chondrocyte matrix and what is aggrecan?
Chondrocyte matrix: aggrecan, type II collagen, type IX collagen.
Aggrecan is a proteoglycan. It has a core protein and bound to them are glycosaminoglycans. Then the inidividual core proteins are noncovalently attached to hyaluronic acid (which is really long)
What are perlecans?
They are proteoglycans, it is found in the basal laminae and is specifically associated with collagen 4.
What is Syndecan
It is found on the cell surface and binds fibroblast growth factors.
Syndecan has a cytoplasmic end which interacts with the underlying cytoskeleton, a core protein extracelluarly which bind heparan sulfate and a transmembrane domain.
It will be nearby the FGF receptor and therefore stabilize the FGF to its receptor.
It can also sense the environment and act intracellularly.
Describe two adhesive glycoproteins
1. Laminin - cross like appearance. They have three different chains and mediate adhesion between matrix and cell surface. Laminin and fibronectin both feature RGD sequences that bind integrins on the cell surface and other extracellular molecules like proteoglycans.
2. Fibronectin: exists as dimers sharing disulfide bonds. It can also bind integrin receptors on the cell surface and bind extracellular proteins.
Essentially link integrins to ECM and have many binding partners.
They are dimers and both subunits are bound by molecules with RGD sequence. The beta subunit binds the cytoskeleton (actin) and can initiate formation of signaling complexes.
It recruits focal adhesion kinase which binds and autophosphorlyates, starting a signal cascade.
What are each of these bound to
alpha 5 beta 1
alpha 6 beta 1
alpha 2 beta 3
alpha 6 beta 4
alphaL beta 2
alpha 5 beta 1: fibronectin
alpha 6 beta 1: laminin
alpha 2 beta 3: fibrinogen, platelets and important for clotting
alpha 6 beta 4: laminin, found in hemidesmosomes.
beta 2: white blood cells and allows them to bind to endothelium.
How and why is integrin regulated?
Describe more specifically the change in beta 2
You don't want some integrins always expressed so integrins have active and inactive states.
It may be as simple as a extracellular signal changing the conformation of the integrin and allowing it to bind ECM.
Important in Beta 2 and beta 3, lymphocyte and platelet.
In beta two there are two cytoplasmic chains. When lymphocytes are bound to selecton, the two chains are pulled apart and the integrin shoots up. Then it can bind to endothelial surface receptors.