Lecture 16 - From Cells to Tissues Flashcards
What does the ECM consist of?
Proteins and proteoglycans.
Functions of the ECM?
- Inert scaffold - stabilise the physical structure of tissues.
- Define the cellular phenotype of cells residing within the ECM.
- Acts as a storage compartment for cell signalling factors.
4 major components of the ECM?
Collagens, proteoglycans, elastin and fibronectin.
What are collagens composed of?
Composed of alpha chains that wrap into a triple helix. These trimers can either be homo- or heteropolymers.
AA sequence?
In the AA sequence glycine is every 3rd residue. The 1st and 2nd AA are either proline, hydroxyproline or hydroxylysine.
Vitamin C is an essential cofactor of collagens. Why is it important? A lack of VC can cause what?
It hydrolyses proline and lysine residues. A lack of VC can result in scurvy.
Main structural role of collagen?
To provide tensile strength to tissues, e.g. bone.
Order of structure formation for collagen fibres?
Alpha chains –> triple helix –> collagen fibrils –> collagen fibres.
Why is glycine AA important for the structure of collagen?
It is small - enables the twisting of chains.
The family of collagens is large and diverse. Name some similarities and differences between the subgroups.
Collagen I - different alpha helices.
Collagen II - homotrimer.
Similarity - they both form trimers.
Steps of collagen synthesis?
- Synthesis of pro-alpha chains via ribosomes. They are called pro-alpha chains because they have propeptides at the N termnius.
- Hydroxylation step - OH residues added to the proline/lysine.
- Glycosylation of alpha chain.
- Assembly of 3 pro-alpha chains.
- Pro collagen triple helix is secreted into the extracellular space.
- Propeptides cleaved. Collagen helix produced. Fibril –> fibre.
Mutations in the alpha 1(I) and alpha 2 (I) genes cause what disease?
Osteogenesis imperfecta (OI). Brittle Bone disease. Bones break easily, blueing of the sclerae of the eye.
Dermatosparaxis (inherited disorder) shows what symptoms?
Causes fragile/loose/hyperflexible skin with bruising and bleeding. Causes by a mutation in the N-terminal propeptidase called ADAMTS-2, means that it cannot remove the propeptides in type I and III collagen.
What does a proteoglycan consist of?
Glucosaminoglycans (GAGs) covalently attached to a core protein (except hyaluronan).
Name the four classes of GAGs.
Hyaluronan (HA), chondroitin sulphate (CS), heparin sulphate (HS) and keratin sulphate (KS).
Why is there a variety of proteoglycans?
Due to different combinations of the core protein with different proteoglycans. The number of GAG chains also affects function, e.g. decorin.
Decorin vs aggrecan
Decorin = chondroitin sulphate and DS. Single GAG chain. Found in connective tissue. Aggrecan = chondroitin sulphate and keratin sulphate. Found in cartilage, mechanical support.
How are proteoglycans synthesised?
Linking sugars (galactose - galactose -xylose) and glucoronic acid (GlcUA) enable the attachment of GAG repeats.
Why is hyaluronan a unique GAG?
It binds to a proteoglycan through link proteins. Consists of repeating disaccharide units and its role is to link proteoglycans.
How do proteoglycans regulate the strength of FGF signalling?
- FGF ligand must bind to its PM receptor.
- Syndecan is a PM proteoglycan that can protrude HS side chains.
- FGF binds to HS –> close proximity to receptors.
- HS proteoglycans are also found in the ECM.
- FGF still binds, but in this instance the ligand is sequestered from its interaction with the receptor, reducing the strength of the FGF signal.
Structure of elastin molecules?
Coiled to allow stretching, Covalently linked monomers.
Multiple mutations in elastin can cause the rare inherited disorder called?
Curtis Laxa. Skin becomes elastic and hangs loosely. Hypermobility of joints.
What is fibronectin and what is its function?
Large glycoprotein. Dimer, multiple different binding domains for proteoglycans, cells and collagen. Helps with matrix organisation.
Where is the basal lamina found?
Between the dermis and epidermis of the skin.
What is the basal lamina composed of?
Entactin, perlecan, laminin and type IV collagen. Form a flattened structure.
How does collagen IV promote the flattened structure of the basal lamina?
It is a triple helix molecule with a globular head region that can form end-on-end and lateral (side by side) associations. Allows criss-cross association of the molecules, forming the unique planar structure.
