Formation of mRNA in the nucleus Initiation of synthesis of pro–α chains with signal sequences by ribosomes Synthesis of pro–α chains on the rER Hydroxylation of proline and lysine residues (vitamin C required) and cleavage of signal sequence from pro-α-chain Glycosylation of specific hydroxylysyl residues in the rER Formation of procollagen triple helix molecules from a C terminus toward the N terminus in a zipper-like manner 1. 2. 3. 4. 5. 6. Stabalization of the triple helix by formation of intraand interchain hydrogen and disulfide bounds and chaparone proteins (e.g., hsp-47) Transport of procollagan molecules to Golgi apparatus Packaging of procollagen molecules by Golgi into secretory vesicles Movement of vesicles to plasma membrane, assisted by molecular motor proteins associated with microtubules 7. 8. 9. 10. 11.  Exocytosis of procollagen molecules 12. Cleavage of trimeric globular Cand helical N-procollagen domains by procollagen Nand C-proteinases 13. Polymerization (self-assembly) of collagen molecules into collagen fibrils (in cove of fibroblast) with development of covalent cross-linking 14. Incorporation of other collagens (e.g,       type V, FACITs, etc.) into collagen fibrils
FIGURE 6.8  Collagen biosynthesis. Schematic representation of the biosynthetic events and organelles participating in collagen synthesis. Bold numbers correspond to the events numbered in collagen biosynthesis listed at the bottom.
Collagen molecule biosynthesis involves a number of intracellular events.
The steps in biosynthesis of almost all fibrillar collagens are similar, but type I collagen has been studied in most detail. In general, the synthetic pathway for collagen molecules is similar to other constitutive secretory pathways used by the cell. The unique features of collagen biosynthesis are expressed in multiple posttranslational processing steps that are required to prepare the molecule for the extracellular assembly process. Thus, we see the following:  Collagen chains are synthesized in the rER as long precursors containing large globular aminoand carboxyterminus propeptides called pro– chains (preprocollagen molecules). The newly synthesized polypeptides are simultaneously discharged into the cisternae of the rER, where intracellular processing begins.
 Within the cisternae of the rER a number of posttranslational modifications of the preprocollagen molecules occur, including the following: 1.
The amino-terminus signal sequence is cleaved.
2.
Proline and lysine residues are hydroxylated while the polypeptides are still in the nonhelical conformation.
Ascorbic acid (vitamin C) is a required cofactor for the addition of hydroxyl groups to proline and lysine residues in pro– chains by the enzymes prolylhydroxylase and lysylhydroxylase; without hydroxylation of proline and lysine residues, the hydrogen bonds essential to the final structure of the collagen molecule cannot form. This explains why wounds fail to heal and bone formation is impaired in scurvy (vitamin C deficiency).
3. O-linked sugar groups are added to some hydroxy -lysine residues (glycosylation) and N-linked sugars are added to the two terminal positions.
4.
The globular structure is formed at the carboxyterminus, which is stabilized by disulfide bonds. Formation of this structure ensures the correct alignment of the three chains during the formation of the triple helix.
5.
A triple helix (beginning from the carboxy-terminus) is formed by three chains, except at the terminals where the polypeptide chains remain uncoiled.
6.