Collagen involves the harmonization of three polypeptide chains into the form of a triple helix. It is characterized by the regular arrangement of amino acids in each of the three chains, with regular repetition and high glycine content—with glycine found at almost every third residue. Under tension, the triple helix coils tight, resisting stretching, and making collagen valuable for structure and support, while giving bones some elasticity. There are at least 27 types of collagen (Zhao 2006).
Humans creatively use collagen to make gelatin for use in foods, cosmetics, photography, and pharmaceuticals (when the three strands are hydrolyzed into random coils); for cosmetic surgery; to construct artificial skin; and to make glue (collagen comes from the Greek word for glue, kolla, and essentially means "glue producer").
The disease scurvy, traced to vitamin C (ascorbic acid) deficiency, results when defective collagen prevents the formation of strong connective tissue. This is tied to the fact that Vitamin C is a critical cofactor in the formation of collagen.
Collagen is common in many types of connective tissue, such as loose connective tissue, dense connective tissue, reticular connective tissue, bone, and cartilage. Connective tissue is one of four primary body tissues of animals, the other three being muscle tissue (contain contractile filaments that move past each other and change the size of the cell), nervous tissue (forming the brain, spinal cord, and peripheral nervous system), and epithelium (covers organs and surface, including outside surface and inside cavities and lumen). Connective tissue is largely a category of exclusion rather than one with a precise definition, but all or most tissues in this category are similarly involved in structure and support. Blood, cartilage, and bone are usually considered connective tissue as well.
Collagen is one of the long, fibrous structural proteins whose functions are quite different from those of globular proteins such as enzymes. Tough bundles of collagen, called "collagen fibers" are a major component of the extracellular matrix that supports most tissues and gives cells structure from the outside, but collagen is also found inside certain cells.
Collagen has 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. Collagen 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 surgery for burns.
Composition and structure
The tropocollagen or "collagen molecule" subunit is a rod about 300 nm long and 1.5 nm in diameter. It is made up of three polypeptide strands, each of which is a left-handed helix, not to be confused with the commonly occurring alpha helix, which is right-handed. These three left-handed helices are twisted together into a right-handed coil, a triple helix, a cooperative 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. This is similar to the situation found with the α-keratins in hair. Collagen's insolubility was a barrier to its study until it was found that tropocollagen from young animals can be extracted because it is not yet fully crosslinked.
Collagen fibrils are collagen molecules packed into an organized overlapping bundle. Collagen fibers are bundles of fibrils.
Collagen has an unusual amino acid composition and sequence:
- Glycine (Gly) is found at almost every third residue (portion, or monomer, of larger molecule)
- Proline (Pro) makes up about 9% of collagen
- There are two uncommon derivative amino acids not directly inserted during translation of mRNA. They are found at specific locations relative to glycine and are modified post-translationally by different enzymes, both of which require vitamin C as a cofactor.
A distinctive feature of collagen is the regular arrangement of amino acids in each of the three chains of the collagen subunits. The sequence often follows the pattern glycine-X-proline or glycine-X-hydroxyproline, where X may be any of various other amino acid residues. Gly-Pro-Hyp (glycine-proline-hydropxyproline) occurs frequently. This kind of regular repetition and high glycine content is found in only a few other fibrous proteins, such as silk fibroin. Approximately 75-80 percent of silk is Gly-Alanine-Gly-Alanine with 10 percent 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 Hyp 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 (Gly) 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 Hyp must point outward. These two amino acids thermally stabilize the triple helix—Hyp 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. Forty nanometer 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.
Types of collagen and associated disorders
Collagen occurs in many places throughout the body. There are 27 or 28 types of collagen described in literature (Zhao 2006).
Collagen diseases commonly arise from genetic defects that affect the biosynthesis, assembly, postranslational modification, secretion, or other processes in the normal production of collagen.
|This is the most abundant collagen of the human body. It is found in tendons, the endomysium of myofibrils. and the organic part of bone. It is present in scar tissue, the end product when tissue heals by repair.
|osteogenesis imperfecta, Ehlers-Danlos_Syndrome
|Found in articular cartilage and hyaline cartilage; makes up 50% of all cartilage protein
|This is the collagen of granulation tissue, and it is produced quickly by young fibroblasts before the tougher type I collagen is synthesized. Found in reticular fiber. Also found in artery walls, intestines, and the uterus
|Found in basal lamina and eye lens. Also serves as part of the filtration system in capillaries and the glomeruli of nephrons in the kidney.
|Found in most interstitial tissue; associated with type I, and associated with placenta.
|Found in most interstitial tissue; associated with type I.
|Ulrich myopathy and Bethlem myopathy
|Forms anchoring fibrils in dermal epidermal junctions.
|Found in some endothelial cells.
|FACIT collagen, found in cartilage, associated with type II and XI fibrils.
|Part of hypertrophic and mineralizing cartilage.
|Found in cartilage.
|FACIT collagen, interacts with type I containing fibrils, decorin and glucosaminoglycans
|transmembrane collagen, interacts with integrin a1b1, fibronectin. and components of basment membranes like nidogen and perlecan.
|Transmembrane collagen, also known as BP180, a 180 kDa protein/
|Bullous Pemphigoid and certain forms of junctional epidermolysis bullosa
|Source of endostatin.
In histology (study of tissue), 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.
The best stain for use in differentiating collagen from other fibers is Masson's trichrome stain.
Collagen I formation
Most collagen forms in a similar manner, but the following process is typical for type I:
- Inside the cell
- Three peptide chains are formed (2 alpha-1 and 1 alpha-2 chain) in ribosomes along the Rough Endoplasmic Reticulum (RER). These peptide chains (known as preprocollagen) have registration peptides on each end; and a signal peptide is also attached to each
- Peptide chains are sent into the lumen of the RER
- Signal peptides are cleaved inside the RER and the chains are now known as procollagen
- Hydroxylation of lysine and proline amino acids occurs inside the lumen. This process is dependent on ascorbic acid (Vitamin C) as a cofactor
- Glycosylation of specific hydroxylated amino acid occurs
- Triple helical structure is formed inside the RER
- Procollagen is shipped to the golgi apparatus, where it is packaged and secreted by exocytosis
- Outside the cell
- Registration peptides are cleaved and tropocollagen is formed by procollagen peptidase.
- Multiple tropocollagen molecules form collagen fibrils, and multiple collagen fibrils form into collagen fibers
- Collagen is attached to cell membranes via several types of protein, including fibronectin and integrin
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 eighteenth century, this condition was notorious among long duration military, particularly naval, expeditions during which participants were deprived of foods containing Vitamin C.
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 (Al-Hadithy et al. 1982).
Industrial and medical 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. Besides food, gelatin has been used in pharmaceutical, cosmetic, and photography industries (GMAP 2005). Nutritionally, collagen and gelatin are considered poor quality protein because they lack adequate amounts of some 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 in support of such claims is lacking.
Collagen historically has been a source of glue. From the Greek for glue, kolla, the word collagen, means "glue producer" and refers to 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 was found to be collagen—carbon dated as more than 8,000 years old—used as a protective lining on rope baskets and embroidered fabrics, to hold utensils together. and in crisscross decorations on human skulls (Walker 1998). Collagen normally converts to gelatin, but is considered to have survived in this case 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.
Collagen has been widely used in cosmetic surgery and certain skin substitutes for burn 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;
- Most medical collagen is derived from cattle, posing the risk of transmitting prion diseases like BSE
- alternatives using the patient's own fat or hyaluronic acid are readily available.
Recently an alternative to bovine-derived collagen has become available. Although expensive, this recombinant human collagen seems to avoid immune reactions described above for collagen derived from livestock. Further, since the human collagen is produced via a yeast expression system, there is no risk of BSE contamination.
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.
Collagen is also sold commercially as a joint mobility supplement.
ReferencesISBN links support NWE through referral fees
- Al-Hadithy, H., D. A. Isenberg, I. E. Addison, A. H. Goldstone, and M. L. Snaith. 1982. Neutrophil function in systemic lupus erythematosus and other collagen diseases. Annals of the Rheumatic Diseases 41: 33-38.
- Gelatin Manufacturers Association of Asia Pacific (GMAP). 2005. Gelatin's advantages. Gelatin Manufacturers Association of Asia Pacific. Retrieved March 16, 2007.
- Walker, A. A. 1998. Oldest glue discovered. Archaeology, May 21, 1998. Retrieved March 16, 2007.
- Zhao, B. 2006. Collagen. DirectScience. Retrieved March 16, 2007.
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