Collagen

From Wikipedia, the free encyclopedia

Tropocollagen triple helix.

Collagen is the main protein of connective tissue in animals and the most abundant protein in mammals, making up about 25% of the total protein content.

1 Uses
- 1.1 Industrial uses
- 1.2 Medical uses
2 Composition and structure
3 Types of collagen and associated disorders
4 Staining
5 Synthesis
6 See also
7 References
8 Additional images
9 External links

[edit] Uses

It 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. 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.

[edit] 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. Besides food, gelatin has been used in pharmaceutical, cosmetic, and photography industries.^[1] 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 does not support these claims.

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, 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.^[2] 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.^[3]

[edit] Medical uses

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, and
most medical collagen is derived from cows, posing the risk of transmitting prion diseases like BSE
alternatives using the patient's own fat, hyaluronic acid or polyacrylamide gel 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.

Collagen is also sold commercially as a joint mobility supplement.

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.

[edit] Composition and structure

The tropocollagen or "collagen molecule" 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, 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 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.

Collagen fibrils are collagen molecules packed into an organized overlapping bundle. Collagen fibers are bundles of fibrils.

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-Hyp, where X may be any of various other amino acid residues. Gly-Pro-Hyp 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 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 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. 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.

[edit] Types of collagen and associated disorders

Collagen occurs in many places throughout the body. There are 28 types of collagen described in literature.

Collagen diseases commonly arise from genetic defects that affect the biosynthesis, assembly, postranslational modification, secretion, or other processes in the normal production of collagen.

Type	Notes	Gene(s)	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, the endomysium of myofibrils and the organic part of bone.	COL1A1, COL1A2	osteogenesis imperfecta, Ehlers-Danlos_Syndrome
II	Articular cartilage and Hyaline cartilage, makes up 50% of all cartilage protein	COL2A1	-
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, intestines and the uterus	COL3A1	-
IV	basal lamina; eye lens. Also serves as part of the filtration system in capillaries and the glomeruli of nephron in the kidney.	COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6	Alport syndrome
V	most interstitial tissue, assoc. with type I, associated with placenta	COL5A1, COL5A2, COL5A3	-
VI	most interstitial tissue, assoc. with type I	COL6A1, COL6A2, COL6A3	Ulrich myopathy and Bethlem myopathy
VII	forms anchoring fibrils in dermal epidermal junctions	COL7A1	epidermolysis bullosa
VIII	some endothelial cells	COL8A1, COL8A2	-
IX	FACIT collagen, cartilage, assoc. with type II and XI fibrils	COL9A1, COL9A2, COL9A3	-
X	hypertrophic and mineralizing cartilage	COL10A1	-
XI	cartilage	COL11A1, COL11A2	-
XII	FACIT collagen, interacts with type I containing fibrils, decorin and glucosaminoglycans	COL12A1	-
XIII	transmembrane collagen, interacts with integrin a1b1, fibronectin and components of basment membranes like nidogen and perlecan.	COL13A1	-
XIV	FACIT collagen	COL14A1	-
XV	-	COL15A1	-
XVI	-	COL16A1	-
XVII	transmembrane collagen, also known as BP180, a 180 kDa protein	COL17A1	Bullous Pemphigoid and certain forms of junctional epidermolysis bullosa
XVIII	source of endostatin	COL18A1	-
XIX	FACIT collagen	COL19A1	-
XX	-	COL20A1	-
XXI	FACIT collagen	COL21A1	-
XXII	-	COL22A1	-
XXIII	-	COL23A1	-
XXIV	-	COL24A1	-
XXV	-	COL25A1	-
XXVII	-	COL27A1	-
XXVIII	-	COL28A1	-

[edit] 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.

The best stain for use in differentiating collagen from other fibers is Masson's trichrome stain.

[edit] Synthesis

[edit] Amino acids

Collagen has an unusual amino acid composition and sequence:

Glycine (Gly) is found at almost every third residue
proline (Pro) makes up about 9% of collagen
two uncommon derivative amino acids not directly inserted during translation of mRNA. Found at specific locations relative to glycine are modified post-translationally by different enzymes, both of which require vitamin C as a cofactor.
- hydroxyproline (Hyp), derived from proline.
- hydroxylysine, derived from lysine. Depending on the type of collagen, varying numbers of hydroxylysines have disaccharides attached to them.

[edit] Collagen I formation

Most collagen forms in a similar manner, but the following process is typical for type I:

Inside the cell
1. 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
2. Peptide chains are sent into the lumen of the RER
3. Signal Peptides are cleaved inside the RER and the chains are now known as procollagen
4. Hydroxylation of lysine and proline amino acids occurs inside the lumen. This process is dependent on Ascorbic Acid (Vitamin C) as a cofactor
5. Glycosylation of specific hydroxylated amino acid occurs
6. Triple helical structure is formed inside the RER
7. Procollagen is shipped to the golgi apparatus, where it is packaged and secreted by exocytosis
Outside the cell
1. Registration peptides are cleaved and tropocollagen is formed by procollagen peptidase.
2. Multiple tropocollagen molecules form collagen fibrils, and multiple collagen fibrils form into collagen fibers
3. Collagen is attached to cell membranes via several types of protein, including fibronectin and integrin.

[edit] 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 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.^[4]