Collagen - Synthesis & Post Translational Modifications

Steps in the Formation of Collagen -

1.Intracellular Steps

2.Extracellular steps

INTRACELLULAR STEPS

1.Translation on Ribosome - 

• synthesized by fibroblasts
• Inside the fibroblasts translation of Gly-X-Y repeat sequence occurs at the rough ER 
• Intracellularly it is secreted as a precursor-Pre-Procollagen

POST - TRANSLATIONAL MODIFICATIONS  - 

• all the next steps are considered as post translational modifications.
• they convert pre-procollagen into mature collagen.

2.Hydroxylation of Proline & Lysine -

• Hydroxylation of proline at position 4 & lysine at position 5 with prolyl hydroxylase and lysyl hydroxylase(dioxygenase enzymes) using molecular oxygen.
• These enzymes contain Fe2+ ion at their active site and require Vitamin C to preserve ion in reduced ferrous state.
• Vitamin C deficiency leads to poor hydroxylation and is the major defect seen in scurvy.

2.Glycosylation of hydroxylation residues-

• After hydroxylation there is glycosylation with galactose & glucose with the help of galactosyl & glucosyl transferase to form Pro-Collagen

3.Formation of intrachain & Interchain disulphide bonds-

• The disulphide bonds are formed mainly in the carboxy and amino terminal ends.

4.Formation of Triple Helix

• The so formed single polypeptide chains are named as alpha chains and they wind around each other to form an triple helix.
• Each strand winds in left hand direction.
• The three strands together wind in right hand direction to form a superhelical cable.
• it is made in such a manner that 3.3 amino acid residues make one turn & each turn is separated by 2.9A.
• The three strand are hydrogen bonded to each other.

EXTRA CELLULAR EVENTS

The formed Pro-collagen is secreted outside the cell to undergo the following modifications -

1.Cleavage 

• There is cleavage of 25-35 kDa portions at both carboxy & amino terminal ends by fibroblast specific peptidases enzymes.
• About 150 amino acids at N terminal & 300 amino acids at carboxy terminal are cleaved.
• Pro-collagen with cleaved ends is called as Tropocollagen.
• Deficiency of peptidases leads to dermatopraxia - a clinical condition where skin is torn easily.

2.Quarter Staggered alignment-

• The formed tropocollagen is arranged in quarter staggered array to form collagen fibre.
• Collagen has triple stranded quarter staggered arrangement.
• this arrangement helps in mineralisation.

3.Formation of intrachain & interchain cross links-

• The collagen fibres are strengthened by covalent cross links by lysine & hydroxylysine residues.with the help of lysyl oxidase converting amino acids into aldehydes forming aldol cross linkages.
• Lysyl oxidase is a copper containing enzyme and in deficiency of copper there is reduced cross linkage of collagen.