Structural Organization
A collagen polypeptide chain contains about 1,000 amino acid residues. The primary structure follows a strict repeating pattern expressed by the formula [Gly-X-Y], where X is most frequently proline and Y is hydroxyproline. Notably, tryptophan and cysteine are completely absent from the molecule, while the proportion of glycine reaches 33%.
The secondary structure of a single chain is an extended left-handed $\alpha$-helix (3 amino acids per turn). Intrachain hydrogen bonds are not formed; instead, stability is maintained by steric repulsion of the pyrrolidine rings of proline. At the next level, three such chains intertwine into a right-handed superhelix — the tropocollagen molecule. Due to its small size, glycine fits perfectly along the central axis of this structure, allowing for tight molecular packing.
Intracellular Stage of Synthesis
Biosynthesis begins on the ribosomes of the rough endoplasmic reticulum in fibroblasts, chondroblasts, or osteoblasts. The synthesized pro-$\alpha$ chain undergoes essential post-translational modifications:
- Hydroxylation. Hydroxyl groups are added to proline and lysine residues. The enzymes (hydroxylases) require oxygen, $\alpha$-ketoglutarate, iron ions ($Fe^{2+}$), and vitamin C, which maintains iron in its active reduced state.
- Glycosylation. Carbohydrate moieties are attached to the newly formed hydroxylysine.
- Assembly. N- and C-terminal propeptides form disulfide bonds, initiating the winding of three chains into the procollagen helix. Chaperone proteins monitor proper folding.
Extracellular Maturation and Fibrillogenesis
Following secretion into the extracellular matrix, specific peptidases cleave the terminal regions of procollagen. The resulting tropocollagen spontaneously assembles into microfibrils. The molecules align in a staggered parallel array with a 1/4 overlap, which appears under electron microscopy as cross-striations with gaps (the sites of initial mineralization).
To achieve ultimate structural strength, covalent cross-links are formed. The copper-dependent enzyme lysyl oxidase (requiring vitamins B3 and B6) oxidizes lysine to allysine, after which these residues spontaneously condense to form aldol and aldimine cross-links, rigidly binding the fiber together.
Types of Collagen and Their Localization
There are multiple recognized types of collagen, which differ in primary structure and function. The main groups include:
- Fibril-forming (Types I, II, III). These withstand immense mechanical stress. Type I forms the basis of bone, dentin, tendons, and the cornea. Type II predominates in cartilage and the vitreous body. Type III forms reticular fibers in parenchymatous organs (liver, kidneys) and blood vessels.
- Network-forming (Type IV). Forms a flexible framework in basement membranes. Its hallmark is the retention of terminal non-collagenous domains and non-helical interruptions that provide elasticity.
- Anchoring fibrils (Type VII). Secure the epidermis to the underlying dermis.
Catabolism and Pathologies
Collagen turns over extremely slowly, and with age, the number of cross-links increases, impairing its degradation. Primary hydrolysis is carried out by tissue collagenase (a zinc-dependent matrix metalloproteinase), cleaving the molecule into two fragments (1/4 and 3/4 length). Lysosomal proteases then complete degradation.
Because of massive gene sizes and complex splicing, collagen synthesis is prone to frequent mutations. Defects lead to severe inherited disorders: Type I mutations cause osteogenesis imperfecta (brittle bone disease), Type III mutations cause Ehlers-Danlos syndrome (aneurysms, joint hypermobility), Type IV mutations cause Alport syndrome (kidney pathology), and Type VII mutations cause epidermolysis bullosa.