Collagen: General Overview
Collagen is the primary structural protein of the extracellular matrix, synthesized by connective tissue cells: fibroblasts, osteoblasts, and chondroblasts. It is a fibrillar protein that provides structural support and mechanical strength to skin, tendons, bones, cartilage, and blood vessel walls.
The collagen polypeptide chain contains about 1,000 amino acid residues. Amino acid composition features:
- every third amino acid is glycine (approx. 33%);
- about 20% are proline and hydroxyproline;
- about 10% are lysine and hydroxylysine;
- cysteine and tryptophan are absent;
- low content of histidine, methionine, and tyrosine.
The primary structure is written as a repeating triplet (Gly–X–Y), where X is most commonly proline, and Y is hydroxyproline or hydroxylysine.
Spatial Organization of the Molecule
The polypeptide chain folds into a left-handed α-helix, which is more extended than the classic α-helix of globular proteins: there are 3 amino acid residues per turn. Three such α-chains wind around each other to form a right-handed triple superhelix, the structural unit of mature collagen known as tropocollagen.
Post-translational modifications
Collagen biosynthesis involves a large number of post-translational modifications. The polypeptide chain is synthesized on ribosomes bound to the membrane of the endoplasmic reticulum as a precursor, preprocollagen. It has an N-terminal signal peptide that directs the chain into the ER lumen, after which it is cleaved off.
Main stages of modification:
- hydroxylation of proline and lysine residues;
- glycosylation of hydroxylysine residues;
- assembly of the triple helix from three pro-α-chains;
- secretion of procollagen into the extracellular space;
- cleavage of N- and C-terminal propeptides (which contain cysteine residues, explaining why mature collagen lacks cysteine);
- assembly of collagen molecules into microfibrils, fibrils, and subsequently collagen fibers.
Proline Hydroxylation and the Role of Vitamin C
The key reaction is catalyzed by prolyl hydroxylase. The enzyme contains an Fe²⁺ ion in its active center and requires α-ketoglutarate and molecular O₂ as cofactors.
During the reaction:
- one oxygen atom is incorporated into the OH group of the proline residue;
- the second oxygen atom is used for the oxidative decarboxylation of α-ketoglutarate, yielding succinate and CO₂.
Ascorbic acid (vitamin C) is required to reduce iron in the active site back to the Fe²⁺ state, as it is periodically oxidized to Fe³⁺ during catalysis. The introduction of an OH group into proline ensures the formation of additional hydrogen bonds between the chains of the triple helix, which dramatically increases the thermal stability and mechanical strength of collagen.
Scurvy: Vitamin C Deficiency
In ascorbic acid deficiency, prolyl hydroxylase loses activity, proline and lysine hydroxylation is impaired, and abnormal collagen with reduced triple-helix stability is synthesized.
Clinical manifestations of scurvy:
- increased vascular fragility and permeability, hemorrhages in the skin and mucous membranes;
- bleeding gums, tooth loosening, and tooth loss;
- impaired wound healing;
- joint pain and bone lesions.
Hyaluronic Acid and Glycosaminoglycans
Hyaluronic acid belongs to glycosaminoglycans — linear polysaccharides of the extracellular matrix composed of repeating disaccharide units (uronic acid and amino sugar residues).
Functional features of hyaluronic acid:
- binds large amounts of water, giving the intercellular substance a jelly-like consistency;
- binds Na⁺ and Ca²⁺ ions, participating in the regulation of water-salt metabolism;
- provides elasticity to cartilage, the vitreous body, and synovial fluid;
- acts as a barrier, impeding the spread of microorganisms.
Clinical Significance: Hyaluronidase and Infections
A number of pathogenic bacteria (e.g., agents of gas gangrene, streptococci, staphylococci) secrete the enzyme hyaluronidase, which degrades hyaluronic acid. Depolymerization of the polysaccharide leads to liquefaction of the connective tissue ground substance, increased permeability, and facilitates the invasion of microorganisms and toxins into tissues.
Key points
- Collagen is built from Gly–X–Y triplets, where Y is frequently hydroxyproline; cysteine and tryptophan are absent.
- The structural unit is a right-handed triple superhelix composed of left-handed α-chains.
- Biosynthesis includes numerous post-translational modifications in the ER and extracellular space.
- Prolyl hydroxylase requires Fe²⁺, O₂, α-ketoglutarate, and ascorbic acid.
- Hydroxyproline stabilizes the triple helix through hydrogen bonds.
- Vitamin C deficiency causes scurvy, characterized by vascular and gum lesions and impaired wound healing.
- Hyaluronic acid is a glycosaminoglycan that retains water and cations in the matrix.
- Bacterial hyaluronidase destroys the matrix, promoting infections, including gas gangrene.