Collagen is the main protein of connective tissue in animals and the most abundant protein in mammals, making up about 40% of the total. It is one of the long, fibrous structural proteins whose functions are quite different from those of globular proteins such as enzymes. It is tough and inextensible, with great tensile strength, and is the main component of cartilage, ligaments, tendons, bone and teeth. Along with soft keratin, it is responsible for skin strength and elasticity, and its degradation leads to wrinkles that accompany aging. It strengthens blood vessels and plays a role in tissue development. It is present in the cornea and lens of the eye in crystalline form. It is also used in cosmetic surgery and burns surgery.
Synthesis
Collagen has an unusual amino acid composition and sequence. Glycine (Gly) is found at almost every third residue, and collagen contains large amounts of proline, (Pro) — as well as two uncommon derivative amino acids not directly inserted during translation of mRNA: hydroxyproline (Hypro) and hydroxylysine. Prolines and lysines at specific locations relative to glycine are modified post-translationally by different enzymes, both of which require vitamin C as a cofactor. Depending on the type of collagen, varying numbers of hydroxylysines have disaccharides attached to them.
Synthetic Pathogenesis
Vitamin C deficiency causes scurvy, a serious and painful disease in which defective collagen prevents the formation of strong connective tissue. Gums deteriorate and bleed, with loss of teeth; skin discolors, and wounds do not heal. Prior to the Eighteen Century, this condition was notorious among long duration military, particularly naval, expeditions during which participants were deprived of fresh fruits and vegetables.
In the human body, a malfunction of the immune system, called an autoimmune disease, results in an immune response in which healthy collagen fibers are systematically destroyed with inflammation of surrounding tissues. The resulting disease processes are called Lupus erythematosus, and rheumatoid arthritis, or collagen tissue disorders. (See references below)
Composition and structure
The tropocollagen subunit is a rod about 300 nm long and 1.5 nm in diameter, made up of three polypeptide strands, each of which is a left-handed helix. They are twisted together into a right-handed coiled coil, a triple helix, a cooperative quaternary structure stabilized by numerous hydrogen bonds. Tropocollagen subunits spontaneously self-assemble, with regularly staggered ends, into even larger arrays in the extracellular spaces of tissues. There is some covalent crosslinking within the triple helices, and a variable amount of covalent crosslinking between tropocollagen helices, to form the different types of collagen found in different mature tissues — similar to the situation found with the α-keratins in hair. Collagen's insolubility was a barrier to study until it was found that tropocollagen from young animals can be extracted because it is not yet fully crosslinked.
A distinctive feature of collagen is the regular arrangement of amino acids in each of the three chains of these collagen subunits. The sequence often follows the pattern Gly-X-Pro or Gly-X-Hypro, where X may be any of various other amino acid residues. Gly-Pro-Hypro occurs frequently. This kind of regular repetition and high glycine content is found in only a few other fibrous proteins, such as silk fibroin. 75-80% of silk is (approximately) -Gly-Ala-Gly-Ala- with 10% serine — and elastin is rich in glycine, proline, and alanine (Ala), whose side group is a small, inert methyl. Such high glycine and regular repetitions are never found in globular proteins. Chemically-reactive side groups are not needed in structural proteins as they are in enzymes and transport proteins. The high content of Pro and Hypro rings, with their geometrically constrained carboxyl and (secondary) amino groups, accounts for the tendency of the individual polypeptide strands to form left-handed helices spontaneously, without any intrachain hydrogen bonding. The triple helix tightens under tension, resisting stretching, making collagen inextensible.
Because glycine is the smallest amino acid, it plays a unique role in fibrous structural proteins. In collagen, Gly is required at every third position because the assembly of the triple helix puts this residue at the interior (axis) of the helix, where there is no space for a larger side group than glycine’s single hydrogen atom. For the same reason, the rings of the Pro and Hypro must point outward. These two amino acids thermally stabilize the triple helix — Hypro even more so than Pro — and less of them is required in animals such as fish, whose body temperatures are low.
In bone, entire collagen triple helices lie in a parallel, staggered array. 40 nm gaps between the ends of the tropocollagen subunits probably serve as nucleation sites for the deposition of long, hard, fine crystals of the mineral component, which is (approximately) hydroxyapatite, Ca5(PO4)3(OH), with some phosphate. It is in this way that certain kinds of cartilage turn into bone. Collagen gives bone its elasticity and contributes to fracture resistance.
Industrial uses
If collagen is partially hydrolyzed, the three tropocollagen strands separate into globular, random coils, producing gelatin, which is used in many foods, including flavored gelatin desserts. Nutritionally, collagen and gelatin are considered poor quality protein because they lack adequate amounts of most of the essential amino acids. Some collagen based dietary supplements are claimed to improve skin and fingernail quality and aid joint health, although mainstream scientific research does not support these claims.
Collagen means "glue producer" (kolla is Greek for glue), derived from the early process of boiling the skin and sinews of horses and other animals to obtain glue. Collagen adhesive was used by Egyptians about 4,000 years ago, and Native Americans used it in bows about 1,500 years ago. The oldest glue in the world, carbon dated as more than 8,000 years old, was found to be collagen — used as a protective lining on rope baskets and embroidered fabrics, and to hold utensils together; also in crisscross decorations on human skulls.[1] Collagen normally converts to gelatin, but survived due to the dry conditions. Animal glues are thermoplastic, softening again upon reheating, and so they are still used in making musical instruments such as fine violins and guitars, which may have to be reopened for repairs — an application incompatible with tough, synthetic plastic adhesives, which are permanent. Animal sinews and skins, including leather, have been used to make useful articles for millennia.
Gelatin-resorcinol-formaldehyde glue (and with formaldehyde replaced by less-toxic pentanedial and ethanedial) has been used to repair experimental incisions in rabbit lungs. (Ann Thorac Surg. 1994 Jun; 57(6): 1622-7)
Medical Uses
Collagen has been widely used in cosmetic surgery and certain skin substitutes for burns patients. The cosmetic use of collagens is declining because:
- there is a fairly high rate of allergic reactions causing prolonged redness and requiring inconspicuous patch testing prior to cosmetic use, and
- most medical collagen is derived from cows, posing the risk of transmitting prion diseases like BSE
- alternatives using the patient's own fat or hyaluronic acid are readily available.
Collagens are still employed in the construction of artificial skin substitutes used in the management of severe burns. These collagens may be bovine or porcine and are used in combination with silicones, glycosaminoglycans, fibroblasts, growth factors and other substances.
Synthetic alternative to collagens and natural ECM have long been clinical goals for non-immunogenic biomaterials. One such MIT-invented family of materials self assembles to form a nanofibrous matrix PuraMatrix Synthetic ECM which can culture anchorage-dependent cells for tissue engineering and bioproduction.
Collagen is also sold commercially as a joint mobility supplement.
Types of collagen
Collagen occurs in many places throughout the body, and occurs in different forms known as types, which include:
- Type I collagen - 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 and the organic part of bone.
- Type II collagen - Articular cartilage
- Type III collagen - This is the collagen of granulation tissue, and is produced quickly by young fibroblasts before the tougher type I collagen is synthesized.
- Type IV collagen - basal lamina; eye lens
- Type V collagen - most interstitial tissue, assoc. with type I, associated with placenta
- Type VI collagen - most interstitial tissue, assoc. with type I
- Type VII collagen - forms ancoring fibrils in dermal epidermal junctions
- Type VIII collagen - some endothelial cells
- Type IX collagen - FACIT collagen, cartilage, assoc. with type II and XI fibrils
- Type X collagen - hypertrophic and mineralizing cartilage
- Type XI collagen - cartilage
- Type XII collagen - FACIT collagen, interacts with type I containing fibrils, decorin and glucosaminoglycans
- Type XIII collagen - transmembrane collagen, interacts with integrin a1b1, fibronectin and components of basment membranes like nidogen and perlecan.
There are 28 types of collagen described in literature until now.
Staining
In histology, collagen is brightly eosinophilic (pink) in standard H&E slides. The dye methyl violet may be used to stain the collagen in tissue samples. The dye methyl blue can also be used to stain collagen and immunohistochemical stains are available if required.
See also
External links and references