Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It 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, in the form of elongated fibrils, is mostly found in fibrous tissues such as tendon, ligament and skin, and is also abundant in cornea, cartilage, bone, blood vessels, the gut, and intervertebral disc.

In muscle tissue, it serves as a major component of the endomysium. Collagen constitutes one to two percent of muscle tissue, and accounts for 6% of the weight of strong, tendinous muscles. Gelatin, which is used in food and industry, is collagen that has been irreversibly hydrolyzed.

History and background

The molecular and packing structures of collagen have eluded scientists over decades of research. The first evidence that it possesses a regular structure at the molecular level was presented in the mid-1930s. Since that time, many prominent scholars, including Nobel laureates Crick, Pauling, Rich and Yonath, and others, including Brodsky, Berman, and Ramachandran, concentrated on the conformation of the collagen monomer. Several competing models, although correctly dealing with the conformation of each individual peptide chain, gave way to the triple-helical "Madras" model, which provided an essentially correct model of the molecule's quaternary structure although this model still required some refinement. The packing structure of collagen has not been defined to the same degree outside of the fibrillar collagen types, although it has been long known to be hexagonal ...or quasi-hexagonal. As with its monomeric structure, several conflicting models alleged that either the packing arrangement of collagen molecules is 'sheet-like' or microfibrillar. The microfibrillar structure of collagen fibrils in tendon, cornea and cartilage has been directly imaged by electron microscopy. In 2006, the microfibrillar structure of adult tendon, as described by Fraser, Miller, and Wess (amongst others), was confirmed as being closest to the observed structure, although it oversimplified the topological progression of neighboring collagen molecules, and hence did not predict the correct conformation of the discontinuous D-periodic pentameric arrangement termed simply: the microfibril.

Molecular structure

The tropocollagen or collagen molecule is a subunit of larger collagen aggregates such as fibrils. At approximately 300 nm long and 1.5 nm in diameter, it is made up of three polypeptide strands (called alpha chains), each possessing the conformation of a left-handed helix (its name is not to be confused with the commonly occurring alpha helix, a right-handed structure). These three left-handed helices are twisted together into a right-handed coiled coil, a triple helix or "super helix", a cooperative quaternary structure stabilized by numerous hydrogen bonds. With type I collagen and possibly all fibrillar collagens if not all collagens, each triple-helix associates into a right-handed super-super-coil referred to as the collagen microfibril. Each microfibril is interdigitated with its neighboring microfibrils to a degree that might suggest they are individually unstable, although within collagen fibrils, they are so well ordered as to be crystalline.

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-Pro-X or Gly-X-Hyp, where X may be any of various other amino acid residues. Proline or hydroxyproline constitute about 1/6 of the total sequence. With glycine accounting for the 1/3 of the sequence, this means approximately half of the collagen sequence is not glycine, proline or hydroxyproline, a fact often missed due to the distraction of the unusual GX₁X₂ character of collagen alpha-peptides. This kind of regular repetition and high glycine content is found in only a few other fibrous proteins, such as silk fibroin. About 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 group. Such high glycine and regular repetitions are never found in globular proteins save for very short sections of their sequence. Chemically-reactive side groups are not needed in structural proteins, as they are in enzymes and transport proteins; however, collagen is not quite just a structural protein. Due to its key role in the determination of cell phenotype, cell adhesion, tissue regulation and infrastructure, many sections of its nonproline-rich regions have cell or matrix association / regulation roles. The relatively high content of proline and hydroxyproline rings, with their geometrically constrained carboxyl and (secondary) amino groups, along with the rich abundance of glycine, accounts for the tendency of the individual polypeptide strands to form left-handed helices spontaneously, without any intrachain hydrogen bonding.

Because glycine is the smallest amino acid with no side chain, 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 help stabilize the triple helix—Hyp even more so than Pro; a lower concentration of them is required in animals such as fish, whose body temperatures are lower than most warm-blooded animals.

Fibrillar structure

The tropocollagen subunits spontaneously self-assemble, with regularly staggered ends, into even larger arrays in the extracellular spaces of tissues. In the fibrillar collagens, the molecules are staggered from each other by about 67 nm (a unit that is referred to as ‘D’ and changes depending upon the hydration state of the aggregate). Each D-period contains four plus a fraction collagen molecules, because 300 nm divided by 67 nm does not give an integer (the length of the collagen molecule divided by the stagger distance D). Therefore, in each D-period repeat of the microfibril, there is a part containing five molecules in cross-section, called the “overlap”, and a part containing only four molecules, called the "gap". The triple-helices are also arranged in a hexagonal or quasihexagonal array in cross-section, in both the gap and overlap regions.

There is some covalent crosslinking within the triple helices, and a variable amount of covalent crosslinking between tropocollagen helices forming well organized aggregates (such as fibrils). Larger fibrillar bundles are formed with the aid of several different classes of proteins (including different collagen types), glycoproteins and proteoglycans to form the different types of mature tissues from alternate combinations of the same key players. For example using AFM –based nanoindentation it has been shown that a single collagen fibril is a heterogeneous material along its axial direction with significantly different mechanical properties in its gap and overlap regions, correlating with its different molecular organizations in these two regions.

Collagen fibrils are semicrystalline aggregates of collagen molecules. Collagen fibers are bundles of fibrils.

Collagen fibrils/aggregates are arranged in different combinations and concentrations in various tissues to provide varying tissue properties. In bone, entire collagen triple helices lie in a parallel, staggered array. Forty nm gaps between the ends of the tropocollagen subunits (approximately equal to the gap region) probably serve as nucleation sites for the deposition of long, hard, fine crystals of the mineral component, which is (approximately) hydroxyapatite, Ca₁₀(PO₄)₆(OH)₂ with some phosphate. It is in this way that certain kinds of cartilage turn into bone. Type I collagen gives bone its tensile strength.

Types and associated disorders

Collagen occurs in many places throughout the body. Over 90% of the collagen in the body, however, is of type one.

So far, 28 types of collagen have been identified and described. The five most common types are:

Collagen I: skin, tendon, vascular ligature, organs, bone (main component 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: cells surfaces, hair and placenta

Collagen-related diseases most commonly arise from genetic defects or nutritional deficiencies that affect the biosynthesis, assembly, postranslational modification, secretion, or other processes involved in normal collagen production.

Notes

Type	|	Gene(s)	Collagen disease>Disorders
Type-I collagen	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, the endomysium of myofibrils, fibrocartilage, and the organic part of bones and teeth. ||	COL1A1, COL1A2	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.	COL2A1	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	COL3A1	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.	COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6	Alport syndrome, Goodpasture's syndrome
V ||	most interstitial tissue, assoc. with type I, associated with placenta	COL5A1, COL5A2, COL5A3	Ehlers–Danlos syndrome (Classical)
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 dystrophica
VIII ||	endothelium>endothelial cells	COL8A1, COL8A2	Posterior polymorphous corneal dystrophy 2
IX ||	FACIT collagen, cartilage, assoc. with type II and XI fibrils	COL9A1, COL9A2, COL9A3	– EDM2 and EDM3
X ||	hypertrophic and mineralizing cartilage	COL10A1	Schmid metaphyseal dysplasia
XI ||	cartilage	COL11A1, COL11A2	Collagenopathy, types II and XI
XII ||	FACIT collagen, interacts with type I containing fibrils, decorin and glycosaminoglycans	COL12A1	–
XIII ||	transmembrane collagen, interacts with integrin a1b1, fibronectin and components of basement 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 ||	MACIT collagen –	COL23A1	–
XXIV ||	–	COL24A1	–
XXV ||	–	COL25A1	–
XXVI ||	–	EMID2	–
XXVII ||	–	COL27A1	–
XXVIII ||	–	COL28A1	–
XXIX ||	epidermal collagen	COL29A1	Atopic dermatitis

In addition to the above mentioned disorders, excessive deposition of collagen occurs in scleroderma.

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.

Synthesis

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 17% of collagen

Collagen contains two uncommon derivative amino acids not directly inserted during translation. These amino acids 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.

* Hydroxyproline (Hyp), derived from proline.

* Hydroxylysine (Hyl), derived from lysine (Lys). Depending on the type of collagen, varying numbers of hydroxylysines are glycosylated (mostly having disaccharides attached).

Cortisol stimulates degradation of (skin) collagen into amino acids.

Collagen I formation

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

#Inside the cell ##Two types of peptide chains are formed during translation on ribosomes along the rough endoplasmic reticulum (RER): alpha-1 and alpha-2 chains. These peptide chains (known as preprocollagen) have registration peptides on each end and a signal peptide. ##Polypeptide chains are released into the lumen of the RER. ##Signal peptides are cleaved inside the RER and the chains are now known as pro-alpha chains. ##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 hydroxylysine residues occurs. ##Triple helical structure is formed inside the endoplasmic reticulum from each two alpha-1 chains and one alpha-2 chain. ##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, via covalent cross-linking (aldol reaction) by lysyl oxidase which links hydroxylysine and lysine residues. Multiple collagen fibrils form into collagen fibers. ##Collagen may be attached to cell membranes via several types of protein, including fibronectin and integrin.

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.

An autoimmune disease such as lupus erythematosus or rheumatoid arthritis may attack healthy collagen fibers.

Many bacteria and viruses have virulence factors which destroy collagen or interfere with its production.

Use

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 fascia, cartilage, ligaments, tendons, bone and skin. Along with soft keratin, it is responsible for skin strength and elasticity, and its degradation leads to wrinkles that accompany ageing. 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. Hydrolyzed collagen can play an important role in weight management, as a protein, it can be advantageously used for its satiating power.

Industrial uses

If collagen is sufficiently denatured, e.g. by heating, the three tropocollagen strands separate partially or completely into globular domains, containing a different secondary structure to the normal collagen polyproline II (PPII), e.g. random coils. This process describes the formation of gelatin, which is used in many foods, including flavored gelatin desserts. Besides food, gelatin has been used in pharmaceutical, cosmetic, and photography industries. From a nutritional point of view, collagen and gelatin are a poor-quality sole source of protein since they do not contain all the essential amino acids in the proportions that the human body requires—they are not 'complete proteins' (as defined by food science, not that they are partially structured). Manufacturers of collagen-based dietary supplements claim that their products can improve skin and fingernail quality as well as joint health. However, mainstream scientific research has not shown strong evidence to support these claims. Individuals with problems in these areas are more likely to be suffering from some other underlying condition (such as normal aging, dry skin, arthritis etc.) rather than just a protein deficiency.

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. 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.

Medical uses

Cardiac applications

The four dense collagen valve rings, the central body of the heart and the cardiac skeleton of the heart are histologically bound to the myocardium. Collagen contribution to heart performance summarily represents an essential, unique and moving solid anchor opposed to the fluid mechanics of blood within the heart. This structure is an impermeable firewall that excludes both blood and electrical influence (except through anatomical channels) from the upper to the lower chambers of the heart. As proof, one could posit that atrial fibrillation almost never deteriorates to ventricular fibrillation. Individual valvular leaflets are held in sail shape by collagen under variable pressure. Calcium deposition within collagen occurs as a natural consequence of aging. Calcium rich fixed points in an otherwise moving display of blood and muscle enable current cardiac imaging technology to arrive at ratios essentially stating blood in cardiac input and blood out cardiac output. Specified imaging such as calcium scoring illustrates the utility of this methodology, especially in an aging patient subject to pathology of the collagen underpinning.

Cosmetic surgery

Collagen has been widely used in cosmetic surgery, as a healing aid for burn patients for reconstruction of bone and a wide variety of dental, orthopedic and surgical purposes. Both human and bovine collagen is widely used as dermal fillers for treatment of wrinkles and skin aging. Some points of interest are: #when used cosmetically, there is a chance of allergic reactions causing prolonged redness; however, this can be virtually eliminated by simple and inconspicuous patch testing prior to cosmetic use, and #most medical collagen is derived from young beef cattle (bovine) from certified BSE (bovine spongiform encephalopathy) free animals. Most manufacturers use donor animals from either "closed herds", or from countries which have never had a reported case of BSE such as Australia, Brazil and New Zealand. #porcine (pig) tissue is also widely used for producing collagen sheet for a variety of surgical purposes. #alternatives using the patient's own fat, hyaluronic acid or polyacrylamide gels which are readily available.

Reconstructive surgical uses

Collagens are widely employed in the construction of artificial skin substitutes used in the management of severe burns. These collagens may be derived from bovine, equine or porcine, and even human, sources and are sometimes used in combination with silicones, glycosaminoglycans, fibroblasts, growth factors and other substances.

Collagen is also sold as a pill commercially as a joint mobility supplement with poor references. Because proteins are broken down into amino acids before absorption, there is no reason for orally ingested collagen to affect connective tissue in the body, except through the effect of individual amino acid supplementation.

Although it cannot be absorbed through the skin, collagen is now being used as a main ingredient for some cosmetic makeup.

Collagen is also frequently used in scientific research applications for cell culture, studying cell behavior and cellular interactions with the extracellular environment. Suppliers such as Trevigen manufacture rat and bovine Collagen I and mouse Collagen IV.

Wound Care Management uses

Collagen is one of the body’s key natural resources and a component of skin tissue that can benefit all stages of the wound healing process. When collagen is made available to the wound bed, closure can occur. Wound deterioration, followed sometimes by procedures such as amputation, can thus be avoided.

Throughout the 4 phases of wound healing, collagen performs the following functions in wound healing: • Guiding Function: Collagen fibers serve to guide fibroblasts. Fibroblasts migrate along a connective tissue matrix. • Chemotactic Properties: The large surface area available on collagen fibers can attract fibrogenic cells which help in healing. • Nucleation: Collagen, in the presence of certain neutral salt molecules can act as a nucleating agent causing formation of fibrillar structures. A collagen wound dressing might serve as a guide for orienting new collagen deposition and capillary growth. • Hemostatic properties: Blood platelets interact with the collagen to make a hemostatic plug.

Fossil record

Because the synthesis of collagen requires a high level of atmospheric oxygen, complex animals may not have been able to evolve until the atmosphere was oxygenic enough for collagen synthesis. The origin of collagen may have allowed cuticle, shell and muscle formation. However, the preservation of collagen in the fossil record is very scarce. There is mounting evidence—which remains controversial—that collagen has been preserved in dinosaur specimens dated as long ago as .

Also worth noting are the actinofibrils, collagen fibers present on the wings of pterosaurs.

Art

Julian Voss-Andreae has created sculptures out of bamboo and stainless steel based on the collagen structure. His piece ''Unravelling Collagen'' is, according to him, a "metaphor for aging and growth".

See also

Hydrolyzed collagen, a common form in which collagen is sold as a supplement.

Animal glue

Gelatine

Fibrous protein

Osteoid, collagen containing component of bone

Lysyl_oxidase and LOXL1, LOXL2, LOXL3, LOXL4 in collagen formation

Collagenase, the enzyme involved in collagen breakdown and remodelling. For more on other proteases that target collagen see The Proteolysis Map

Ehlers-Danlos Syndrome

Hypermobility Syndrome

Marfan Syndrome, a genetic disease with defective fibrillin 1

References

External links

The Collagen Protein

Variant Collagen Products Range

12 types of collagen

Database of type I and type III collagen mutations

Science.dirbix Collagen

Collagen Stability Calculator

Computer-generated animations of the assembly of Type I and Type IV Collagens

Integrin-Collagen interface, PMAP (The Proteolysis Map)—animation

Integrin-Collagen binding model, PMAP (The Proteolysis Map)—animation

Collagen-Integrin atomic detail, PMAP (The Proteolysis Map)—animation

Category:Structural proteins Category:Edible thickening agents Category:Integrins *

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