Ch 7- Fibrous Proteins Fibrous Collagen Protein

Fibrous protein

Collagen Protein

Collagen

Fibrous protein with three intertwined polypeptide chains

Location of collagen

CT such as tendons, cartilage, bone, the cornea of the eye, skin etc

Function of collagen

provide strength to tissue

Most abundant fibrous protein

Collagen

Five groups of collagen depending on how the alpha chains are combined

1. Fibril forming chains
2. Network forming
3. Fibril-associated collagen

Fibril forming chains

linear with a banding pattern

Network forming

constitute basement of cellular membrane

Fibril-associated collagen

found in ECM

Collagen primary structure

- Repeating tripeptide unit
- Gly-X-Y, where X and Y are amino acids
- Often proline and 4- Hydorxy-proline in X and Y positions

Hydroxylation of protein

post translational modification of protein eg formation of hydroxyprolyl residue
- Done by prolyl hydroxylase
- Vitamin C is extremely important for this modification

Secondary structure of collagen

- A chain (not a-helix)
- A left-handed helix, with three amino acid residues per turn
- Gly is ideal for this structure due to its very small side chain (one H) while the Pro and 4-Hydroxyproline residues permit the sharp twisting
- R- group exposed in this chain

Tertiary structure of collagen

The structure of a single collagen chain

Quarternary Structure of collagen

- first level- three separate collagen polypeptides (a-chains) are supertwisted about each other in a right-hand manner
- the formed triple helix is called tropocollagen
- tropocollagen can associate together to form higher order structure (fibril)

Synthesis of Collagen

1. In the nucleus the genes coding from pro alpha 1 and pro a2 chain are transcribed into mRNA
2. mRNA sent to rough endoplasmic reticulum where the translation occurs and the prepro a polypeptide chains are extruded into its lumen and the signal sequence is removed
3. Selected Proline and lysine are modified by hydroxylation
4. Selected hydroxylysine residues are glycosylated with glucose and galactose
5. the pro-a- chains begin to assemble
- Intrachain and interchain disulfide bonds form the C terminus propeptide extension
6. A triple helix is formed and pro collagen is formed
7. The pro collagen is secreted form a Golgi vesicle into the ECM (crosses the membrane)
8. The cleavage of the pro collagen the N (amino) and C terminus propeptides are removed so only the tropocollagen remains

Assembly of collagen fibrils

- Tropocollagen remains with sugar modification
- Self assembles as a collagen fibril
- Within this fibril the different tropocollagen molecules will be cross linked to make it very resistant

Structure-function relationship in fibrous proteins eg collagen

- Fibril: the tropocollagen molecules arranged into continuous long fibres
- Extremely high tensile strength
- Fibres cross linked by unusual types of covalent bonds involving Lys, OH-Lys (5-hydroxylysine) or His residues (X and Y positions)
- The cross links give strength and rigidity to collagen fibres
- Hydroxyproline can form H-bonds that provide stability to the fibres

Disease caused by defective collagen structure

Scurvy

Cause of scurvy

- Due to Vitamin C deficiency
- Vit C as a cofactor of the enzymes proline and lysine hydroxylase the enzymes generating hydroxylated proline and lysine
- General degeneration of CT

Symptoms of scurvy

- Numerous small haemorrhages caused by fragile blood vessels
- Tooth loss
- Poor wound healing and reopening of old wounds
- Bone degeneration
- Eventually heart failure

Collagenopathies

- Ehler-Danlos syndrome
- Osteogenesis imperfecta - brittle bone syndrome

Ehler Danlos Syndrome features

- Extremely loose joints, hyperelastic skin, skin that bruises easily and easily damaged blood vessels

What does Ehler Danlos Syndrome effect?

- Defect in processing collagen, no secretion of collagen and degradation
- Affects collagen 1. 3 or 5

Osteogenesis imperfecta - brittle bone syndrome

- Abnormal bone formation in babies
- Decrease production of type 1 (alpha 1 and 2) collagen
- Mutations often result in substitution of glycine by other amino acids eg Cys, Arg prevents formation of helix and final triple helix structure- no resistance