Collagen is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content.
Collagen is composed of a triple helix [1]. The triple-helical domain structure of collagens consists of three distinct α-chains and earns collagen the name “tropocollagen” . Each of these chains contain a characteristic L-handed amino acid sequence of polyproline, often termed as polyproline type II helix. The proper folding of each of these chains requires a glycine residue to be present in every third position in the polypeptide chain. For example, each α-chain is composed of multiple triplet sequences of of Gly-Y-Z in which Y and Z can be any amino acid. Y is commonly found as proline and Z is usually present as hydroxyproline. The presence of hydroxyproline in the Y position is also thought to contribute to the stability of the helical form [4].
The various collagens are distinguished by the ability of their helical and nonhelical regions to associate into fibrils, to form sheets, or to cross-link different collagen types.
Most collagen is fibrillar and composed of type I molecules. A two-dimensional network of type IV collagen is unique to the basal lamina. Fibrous type collagen molecules (e.g., types I, II, and III) assemble into fibrils that are stabilized by covalent aldol cross-links [2].
Procollagen chains are modified and assembled into a triple helix in the ER.
Helix formation is aided by disulfide bonds between N- and C-terminal propeptides, which align the polypeptide chains in register.
Generally, the propeptides are removed after secretion, and then collagen fibrils form in the extracellular space.
Fibrous collagen has specific structural requirements and is very susceptible to mutation, especially in glycine residues. Because mutant collagen chains can affect the function of wild-type ones, such mutations have a dominant phenotype [2].
Molecular biology of Collagen, a major structural protein. Figure ©2000 by Griffiths et al
Collagen synthesis
Inside fibroblasts:
1. Collagen α chains (preprocollagen) translated on RER––usually Gly-X-Y polypeptide (X and Y are proline, hydroxyproline, or hydroxylysine).
2. ER →hydroxylation of specific proline and lysine residues (requires vitamin C).
3. Golgi →glycosylation of pro-α-chain lysine residues and formation of procollagen (triple helix of 3 collagen α chains).
4. Procollagen molecules are exocytosed into extracellular space.
Outside fibroblasts:
5. Procollagen peptidases cleave terminal regions of procollagen, transforming procollagen into insoluble tropocollagen.
6. Many staggered tropocollagen molecules are reinforced by covalent lysine-hydroxylysine cross-linkage (by lysyl oxidase) to make collagen fibrils. Lysyl oxidase require copper (Cu++) for its activity.
Most common types are:
- Collagen I: Skin, tendon, vascular ligature, organs, bone (main component of the organic part of bone)
- Collagen II: Cartilage (main component of cartilage)
- Collagen III: Reticulate (main component of reticular fibers), commonly found alongside type I.
- Collagen IV: Forms bases of cell basement membrane
- Collagen V: Cell surfaces, hair and placenta
Mnemonics: Type I: BONE | Type II: carTWOlage. | Type III: ArTHREE (Artery). | Type IV: Under the floor (basement membrane) [5].
| Type | Notes | Disorders |
| I | This is the most abundant collagen of the human body. It is present in scar tissue, the end product when tissue heals by repair. It is found in tendons, skin, artery walls, cornea, the endomysium of myofibrils, fibrocartilage, and the organic part of bones and teeth. | Osteogenesis imperfecta, Ehlers–Danlos syndrome, Infantile cortical hyperostosis aka Caffey’s disease |
| II | Hyaline cartilage, makes up 50% of all cartilage protein. Vitreous humour of the eye. | Collagenopathy, types II and XI |
| III | This is the collagen of granulation tissue, and is produced quickly by young fibroblasts before the tougher type I collagen is synthesized. Reticular fiber. Also found in artery walls, skin, intestines and the uterus | Ehlers–Danlos syndrome, Dupuytren’s contracture |
| IV | Basal lamina; eye lens. Also serves as part of the filtration system in capillaries and the glomeruli of nephron in the kidney. | Alport syndrome, Goodpasture’s syndrome |
| V | Most interstitial tissue, assoc. with type I, associated with placenta | Ehlers–Danlos syndrome (Classical) |
| VI | Most interstitial tissue, assoc. with type I | Ulrich myopathy, Bethlem myopathy, Atopic dermatitis |
| VII | Forms anchoring fibrils in dermoepidermal junctions | Epidermolysis bullosa dystrophica |
| VIII | Some endothelial cells | Posterior polymorphous corneal dystrophy 2 |
| IX | FACIT collagen, cartilage, assoc. with type II and XI fibrils | EDM2 and EDM3 |
| X | Hypertrophic and mineralizing cartilage | Schmid metaphyseal dysplasia |
| XI | Cartilage | Collagenopathy, types II and XI |
In addition to the above mentioned disorders, excessive deposition of collagen occurs in scleroderma.
Functions of collagen:
1. Collagens serve within the body to a large extent for the maintenance of the structural integrity of tissues and organs.
2. Collagens contribute to the entrapment, local storage and delivery of growth factors and cytokines and therefore play important roles during organ development, wound healing and tissue repair.
3. Some additional features of collagens, such as biodegradability, low immunogenicity and the possibilities for large-scale isolation make them interesting compounds for a widespread industrial use in medicine, cosmetics or food industry[3].
Diseases:
- Osteogenesis imperfecta – Caused by a mutation in type 1 collagen, dominant autosomal disorder, results in weak bones and irregular connective tissue, some cases can be mild while others can be lethal, mild cases have lowered levels of collagen type 1 while severe cases have structural defects in collagen.
- Chondrodysplasias – Skeletal disorder believed to be caused by a mutation in type 2 collagen, further research is being conducted to confirm this.
- Ehler-Danlos Syndrome – Ten different types of this disorder which lead to deformities in connective tissue, some types can be lethal that lead to the rupture of arteries, each syndrome is caused by a different mutation, for example type four of this disorder is caused by a mutation in collagen type 3.
- Alport syndrome – Can be passed on genetically, both an autosomal dominant and autosomal recessive disorder, sufferers have problems with their kidneys and eyes, loss of hearing can also develop in during the childhood or adolescent years.
- Osteoporosis – Not inherited genetically, brought on with age, associated with reduced levels of collagen in the skin and bones, growth hormone injections are being researched as a possible treatment to counteract any loss of collagen.
- Knobloch syndrome – Caused by a mutation in the collagen XVIII gene, patients present with protrusion of the brain tissue and degeneration of the retina, an individual who has family members suffering from the disorder are at an increased risk of developing it themselves as there is a hereditary link [1].
- Scurvy – Scurvy is a disease resulting from a deficiency of vitamin C, which is required for the synthesis of collagen in humans. Symptoms include malaise , lethargy, skin changes with roughness, easy bruising and petechiae, gum disease, loosening of teeth, poor wound healing, and emotional changes.
REFERENCES:
1. http://en.wikipedia.org/wiki/Collagen
2. http://www.ncbi.nlm.nih.gov/books/NBK21582/
3. https://ueaeprints.uea.ac.uk/1112/1/2003_Gelse_et_al_Collagens_structure_function_and______biosynthesis.pdf
4. http://proteopedia.org/wiki/index.php/Collagen_Structure_%26_Function
5. First Aid for the USMLE Step 1.
Last revised: 12/12/2012
Medical Notebook 