collagen

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Dictionary: col·la·gen (kŏl'ə-jən) pronunciation

The fibrous protein constituent of bone, cartilage, tendon, and other connective tissue. It is converted into gelatin by boiling.

[Greek kolla, glue + –GEN.]

collagenic col'la·gen'ic (-jĕn'ĭk) or col·lag'e·nous (kə-lăj'ə-nəs) adj.

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Sci-Tech Encyclopedia: Collagen

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The major fibrous protein in animals, present in all types of multicellular animals and probably the most abundant animal protein in nature. It is estimated that collagen accounts for about 30% of the total human body protein. Collagen is located in the extracellular matrix of connective tissues. It is part of the interacting network of proteoglycans and proteins that provides a structural framework for both soft and calcified connective tissues. By self-associating into fibrils and by binding to proteoglycans and other matrix components, collagen contributes to tissue integrity and mechanical properties. Collagen interacts with cells through the integrin cell receptors and mediates cellular adhesion and migration. Important roles for collagen have been identified in development, wound healing, platelet aggregation, and aging. Its commercial importance in leather and the production of gelatin and glue have long been recognized. More recently, it is being used as a basis for biomaterials. Examples of its biomedical applications include injectable collagen to lessen facial wrinkles and defects; surgical collagen sponges to increase blood clotting; and artificial skin for the treatment of burns. See also Gelatin.

The classification of an extracellular matrix protein as a collagen is based on the presence of a domain with a distinctive triple-helical conformation. The collagen triple helix consists of three polypeptide chains supercoiled about a common axis and linked by hydrogen bonds. At least 19 distinct molecules have been classified as collagens, and specific types are associated with particular tissues. The most prevalent and well-studied collagens belong to the fibril-forming or interstitial collagen family. The molecules in a fibril are covalently cross-linked by an enzymatic mechanism to strengthen and stabilize them. Inhibition of the enzyme involved in cross-linking results in a dramatic decrease in the tensile strength of tissues, a condition known as lathyrism.

Type I is the most common fibril-forming collagen. Its fibrils make up the mineralized matrix in bone, the strong parallel bundles of fibers in tendon, and the plywoodlike alternating layers in the transparent cornea. Type II is the major fibril-forming collagen in cartilage, while type III is found in blood vessels and skin, together with type I. Basement membranes, which serve to separate cell layers and act as filtration barriers, contain a distinctive group of collagens, denoted as type IV collagens, which are organized into a network or meshlike sheet structure. In the kidney glomerulus, the network based on type IV collagen acts as a filter to determine which molecules will pass from the blood into the urine. See also Bone; Connective tissue; Fibrous protein.

An orderly breakdown of collagen is necessary during development and tissue remodeling. For instance, following childbirth, the uterus reduces in size, which involves a massive degradation of collagen. An abnormal increase in the degradation of cartilage collagen is seen in osteoarthritis. Collagen breakdown also appears to be essential for tumor metastases. A number of hereditary diseases have been shown to be due to mutations in specific collagen genes. Osteogenesis imperfecta (brittle bone) disease is characterized by fragile bones and is due to mutations in type I collagen. Some cartilage disorders are caused by mutations in type II collagen. Ruptured arteries are found in Ehlers-Danlos syndrome type IV, which arises from mutations in type III collagen.

World of the Body: collagen

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The word collagen means ‘glue-producing’. Collagen in the body does indeed help to hold it all together, but the notion of glue is not very apt. It strengthens and connects things with a network of tough fibres, rather than sticking them to each other — more like a cat's cradle than an adhesive. Collagen is the protein which forms the ubiquitous white fibres in all the connective tissues of the body, including bone, teeth, cartilage, and tendons; the skin; and all the sheaths, partitions, and supporting frameworks which abound in all organs and tissues. The exception is the central nervous system, which has its own different variety of internal supporting tissue — the glia — though there is collagen in the membranes which cover the brain and spinal cord.

Collagen is one of the ‘structural proteins’ (the other widespread one is elastin), which provide support to the tissues. By crude analogy with string, the principal mechanical property of collagen is its ability to resist distending force (tensile strength), which is vastly greater than its ability to resist compression or twisting (compression and torsion strengths). The tensile strength of collagen is so high as to be comparable, weight for weight, with that of steel. Elastin, by contrast, has a low tensile strength but the important mechanical properties of distensibility and resilience: the capability for relatively long range stretching under load and for returning to the original dimensions when the distending force is removed. Collagen can stretch only by about 2% without damage.

Collagen and elastin fibres often co-exist, notably in tissues which regularly undergo considerable changes in shape, such as skin, lungs, and blood vessels. The essentially inextensible, high tensile strength collagen is able to exist and function alongside the elastic fibres simply by having considerable slack. This can easily be illustrated if you pinch up the skin on the back of the hand: it returns to its original shape on release by virtue of the elastic fibres (a property progressively impaired in old age due to degeneration of the elastic fibres, with consequent increase in skin wrinkling). Now with the fingertips push the same skin on the back of the hand sideways and note that it slides quite freely until displacement comes to a distinct halt (when the collagen has used its slack and the tough fibres are pulled into alignment, resisting the distending force).

Collagen is synthesized by fibroblasts, the living cells present in all connective tissue, so named because they generate fibres — of collagen. There are in fact several types, with minor variations of molecular structure. Like all proteins, collagens are constructed from amino acid units; they are all glycoproteins, meaning that glucose and other simple sugars are attached to the amino acid chains. Each long, thin molecule consists of three chains of over 1000 units; each chain is helical, and the three in turn form a triple helix. A molecule is about 300 nm long — over 3000 end-to-end would measure 1 mm — but in fully-formed collagen they overlap lengthwise, and are also linked side to side, providing longer, wider, and very tough fibres. Again like all proteins in the body, collagen has a finite life span after which it is degraded to the constituent amino acids and replaced by new fibres. The synthesis within the fibroblasts is a complex process; the three chains are separately assembled, and then wound into the triple helix, which is extruded. Once outside the cell, the molecules aggregate and forge links as described.

The complexity of collagen synthesis involves multiple enzymes, so that a congenital deficiency of any of these can lead to some disorder of its formation. This accounts for there being a wide variety of clinical syndromes associated with such disorders: there can be fragile bones, with fractures from minimal trauma; fragile blood vessels with widespread bruising; dental defects; readily dislocating joints; a bent or twisted spine; thin, hyperelastic skin; and poor wound healing. Apart from these inborn defects, deprivation of ascorbic acid (vitamin C) at any time of life interferes with a step in collagen synthesis; the resulting bleeding, bruising, and poor healing are part of the picture of scurvy.

With ageing, habitually exposed areas of skin in white-skinned people show broken and disordered collagen fibres, related to the effects of UV light. Deficient replacement of collagen also contributes to thinning and wrinkling of the skin, and, together with mineral loss, to osteoporosis — decreasing bone mass.

These changes suggest that the continuous production of new fibroblasts, and by them of new collagen, progressively declines. Fibroblasts in culture outside the body divide again and again, but do not continue to replicate indefinitely. When such cultures from different animal species are compared, it is found that the number of cell divisions is related to the lifespan of each species, and is also related inversely to the age of the donor from any one species: a finding of considerable interest in the study of the ageing process.

— Hugh Elder, Sheila Jennett

Uses

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 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. Hydrolyzed collagen can play an important role in weight management, as a protein, it can be advantageously used for its satiating power.^{[citation needed]}

Industrial uses

If collagen is sufficiently hydrolyzed, 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.^[4] 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.^[5] 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.^[6]

Medical uses

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. 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 gel are readily available.

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 commercially as a joint mobility supplement^[7]. 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.

Recently an alternative to animal-derived collagen has become available. Although expensive, this human collagen, derived from donor cadavers, placentas and aborted fetuses, may minimize the possibility of immune reactions.

Although it cannot be absorbed through the skin, collagen is now being used as a main ingredient for some cosmetic makeup.^[8]

Conformation and structure

Collagen structure is complex. Its conformation can be considered at the monomeric level (individual collagen molecules) and/or at its aggregate level (how the trimers are arranged), i.e. their packing structure (fibrils, networks, etc.—see below)^[9].

History and background

The molecular and packing structures of collagen have eluded scientists for decades; the first evidence that it possess a regular structure at the molecular level was presented in the mid-1930s ^[10] ^[11]. Since that time many prominent scholars, including (but not limited to) Nobel laureate Crick, and Pauling, Rich, Yonath, 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 ^[12]^[13]^[14] although this model still required some refinement ^[15]^[16]^[17]^[18]. 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 ^[19]^[20]^[21]. As with its monomeric structure, several conflicting models alleged that either the packing arrangement of collagen molecules is ‘sheet-like’ or microfibrillar.^[22]^[23] Recently it was confirmed that the microfibrillar structure as described by Fraser, Miller, Wess (amongst others) was closest to the observed structure, although it over-simplified 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^[24]

Molecular structure

The tropocollagen or "collagen molecule" is a subunit of larger collagen aggregates such as fibrils. It is approximately 300 nm long and 1.5 nm in diameter, made up of three polypeptide strands (called alpha peptides), 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 that is referred to as the collagen microfibril. Each microfibril is interdigitated with its neighboring microfibrils to a degree that might suggest that 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-Y or Gly-X-Hyp, where X and Y 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 that approximately half of the collagen sequence is not glycine, proline or hydroxyproline, a fact often missed due to the distraction of the unusual GXY 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. 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 non-proline 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^[25]^[26]. In the fibrillar collagens, the molecules are staggered from each other by about 67nm (a unit that is referred to as ‘D’ and changes depending upon the hydration state of the aggregate). Each D-period contains 4 and a fraction collagen molecules. This is 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 4 molecules.^[24] The triple-helices are also arranged in a hexagonal or quasi-hexagonal array in cross-section, in both the gap and overlap regions.^[24]^[27].

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)^[28]. 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^[29]. Collagen's insolubility was a barrier to the study of monomeric collagen until it was found that tropocollagen from young animals can be extracted because it is not yet fully crosslinked. However, advances in microscopy techniques (Electron Microscopy (EM) and Atomic Force Microscopy (AFM)) and X-ray diffraction have enabled researchers to obtain increasingly detailed images of collagen structure in situ. These later advances are particularly important to better understanding the way in which collagen structure affects cell-cell and cell-matrix communication and how tissues are constructed in growth and repair, and changed in development and disease^[30]^[31].

Collagen fibrils are semi-crystalline 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. 40 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. The 29 types of collagen have thus far been identified and described in literature. Over 90% of the collagen in the body, however, are of type I, II, III, and IV.

Collagen One: skin, tendon, vascular, ligature, organs, bone (main component of bone)
Collagen Two: cartilage (main component of cartilage)
Collagen Three: reticulate (main component of reticular fibers), commonly found alongside type I.
Collagen Four: forms bases of cell basement membrane

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, 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
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	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	some 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^[32]

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

Action of lysyl oxidase (in French)

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
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, derived from lysine. Depending on the type of collagen, varying numbers of hydroxylysines have disaccharides attached to them.

Cortisol stimulates degradation of amino acid from skin collagen.^[33]

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.

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.^[34]

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

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.^[35] The origin of collagen may have allowed cuticle, shell and muscle formation. However, the preservation of collagen in the fossil record is very scarce.^[36] There is mounting evidence—which remains controversial—that collagen has been preserved in dinosaur specimens dated as long ago as 80 million years ago.^[37]

Art

Julian Voss-Andreae's sculpture Unravelling Collagen (2005), stainless steel, height 11'3" (3.40 m).

Julian Voss-Andreae has created sculptures based on the collagen structure out of bamboo and stainless steel. His piece "Unravelling Collagen" is, according to the artist, a "metaphor for aging and growth"^[38]^[39].

References

^ Gloria A. Di LulloDagger , Shawn M. Sweeney, Jarmo Körkkö, Leena Ala-Kokko, and James D. San Antonio; Mapping the Ligand-binding Sites and Disease-associated Mutations on the Most Abundant Protein in the Human, Type I Collagen; J. Biol. Chem., Vol. 277, Issue 6, 4223-4231, February 8, 2002
^ Muller, Werner E.G. The Origin of Metazoan Complexity: Porifera as Integrated Animals. Integrated Computational Biology, 43:3–10, 2003.
^ Sikorski, Zdzisław E. (2001) Chemical and Functional Properties of Food Proteins. CRC Press. p. 242
^ Gelatin's Advantages: Health, Nutrition and Safety
^ Oldest Glue Discovered
^ Ann Thorac Surg. 1994 Jun; 57(6): 1622–7
^ Hydrolyzed Collagen pills usages
^ http://www.articlesbase.com/skin-care-articles/can-collagen-be-absorbed-into-the-skin-or-is-it-all-just-one-big-hoax-674325.html
^ Observe these structural aspect from a 3D perspective at http://www.messiah.edu/molscilab/Jmol/collagen/collagen_index.htm
^ Wyckoff, R., R. Corey, and J. Biscoe, X-ray reflections of long spacing from tendon. Science, 1935. 82: p. 175–176.
^ Clark, G., Parker, E., Schaad, J. and Warren, W.J, New measurements of previously unknown large interplaner spaceings in natural materials. J. Amer. Chem. Soc, 1935. 57: p. 1509–1509.
^ GNR — A Tribute - Resonance - October 2001
^ http://www.proteinscience.org/cgi/reprint/10/8/1689.pdf
^ G.N. Ramachandran - Nature Structural & Molecular Biology
^ Fraser, R.D., T.P. MacRae, and E. Suzuki, Chain conformation in the collagen molecule. J Mol Biol, 1979. 129(3): p. 463–81
^ Okuyama, K., et al., Crystal and molecular structure of a collagen-like polypeptide (Pro-Pro-Gly)10. J Mol Biol, 1981. 152(2): p. 427–43.
^ Traub, W., A. Yonath, and D.M. Segal, On the molecular structure of collagen. Nature, 1969. 221(5184): p. 914–7.
^ Bella, J., M. Eaton, B. Brodsky, and H.M. Berman, Crystal and molecular structure of a collagen-like peptide at 1.9 A resolution. Science, 1994. 266(5182): p. 75–81.
^ Hulmes, D.J. and A. Miller, Quasi-hexagonal molecular packing in collagen fibrils. Nature, 1979. 282(5741): p. 878–80.
^ Jesior, J.C., A. Miller, and C. Berthet-Colominas, Crystalline three-dimensional packing is general characteristic of type I collagen fibrils. FEBS Lett, 1980. 113(2): p. 238–40.
^ Fraser, R.D.B. and T.P. MacRae, Unit cell and molecular connectivity in tendon collagen. Int. J. Biol. Macromol., 1981. 3: p. 193–200.
^ Fraser, R.D., T.P. MacRae, and A. Miller, Molecular packing in type I collagen fibrils. J Mol Biol, 1987. 193(1): p. 115–25.
^ Wess, T.J., et al., Molecular packing of type I collagen in tendon. J Mol Biol, 1998. 275(2): p. 255–67.
^ ^a ^b ^c Orgel, J.P., et al., "Microfibrillar structure of type I collagen in situ". Proc Natl Acad Sci U S A, 2006. 103(24): p. 9001–5.
^ Hulmes, D.J., Building collagen molecules, fibrils, and suprafibrillar structures. J Struct Biol, 2002. 137(1-2): p. 2–10
^ Hulmes, D.J., The collagen superfamily—diverse structures and assemblies. Essays Biochem, 1992. 27: p. 49–67.
^ Hulmes, D.J. and A. Miller, Quasi-hexagonal molecular packing in collagen fibrils. Nature, 1979. 282(5741): p. 878-80.
^ Perumal, S., O. Antipova, and J.P. Orgel, Collagen fibril architecture, domain organization, and triple-helical conformation govern its proteolysis. Proc Natl Acad Sci U S A, 2008. 105(8): p. 2824–9.
^ Hulmes, D.J., The collagen superfamily—diverse structures and assemblies. Essays Biochem, 1992. 27: p. 49–67.
^ Sweeney, S.M., et al., Candidate cell and matrix interaction domains on the collagen fibril, the predominant protein of vertebrates. J Biol Chem, 2008. 283(30): p. 21187–97.
^ Twardowski, T., et al., Type I collagen and collagen mimetics as angiogenesis promoting superpolymers. Curr Pharm Des, 2007. 13(35): p. 3608–21.
^ Söderhäll C, Marenholz I, Kerscher T, Rüschendorf F, Esparza-Gordillo J, et al., Variants in a Novel Epidermal Collagen Gene (COL29A1) Are Associated with Atopic Dermatitis. PLoS Biology Vol. 5, No. 9, e242 doi:10.1371/journal.pbio.0050242
^ Houck, J.C.; Sharma, V.K.; Patel, Y.M.; Gladner, J.A. (1968) “Induction of Collagenolytic and Proteolytic Activities by AntiInflammatory Drugs in the Skin and Fibroblasts”. Biochemical Pharmacology 17: 2081,
^ AJR article about lupus and other collagen disorders
^ http://facstaff.gpc.edu/~pgore/geology/geo102/cambrian.htm
^ We, KENNETH M. TO (1996). "Fossil preservation in the Burgess Shale". Lethaia 29: 107. doi:10.1111/j.1502-3931.1996.tb01844.x. edit
^ Schweitzer, M. H.; Wenxia Zheng,1 Chris L. Organ,3 Recep Avci,4 Zhiyong Suo,4 Lisa M. Freimark,5 Valerie S. Lebleu,6,7 Michael B. Duncan,6,7 Matthew G. Vander Heiden,8 John M. Neveu,9 William S. Lane,9 John S. Cottrell,10 John R. Horner,11 Lewis C. Cantley,5,12 Raghu Kalluri,6,7,13 John M. Asara5,14,* (2009). "Biomolecular Characterization and Protein Sequences of the Campanian Hadrosaur B. Canadensis". Science 324: 626. doi:10.1126/science.1165069. edit
^ Ward, Barbara (April 2006). "'Unraveling Collagen' structure to be installed in Orange Memorial Park Sculpture Garden". Expert Rev. Proteomics 3 (2): 174. doi:10.1586/14789450.3.2.169. http://www.future-drugs.com/doi/pdf/10.1586/14789450.3.2.169.
^ Interview with J. Voss-Andreae "Seeing Below the Surface" in Seed Magazine

External links

Wikimedia Commons has media related to: Collagen

Histology: connective tissue

Classification

Proper	Loose/areolar · Dense/Fibrous · Adipose (Brown, White) · Reticular

Embryonic	Mucous · Mesenchymal

Specialized	Cartilage · Bone · Blood · Tendon

Composition

Extracellular
matrix
(noncellular)

Ground substance	Tissue fluid

Fibers	Reticular fibers: Collagen Elastic fibers: Fibrillin (FBN1, FBN2, FBN3)

Cells

Resident	Fibroblast · Adipocyte · Chondroblast · Osteoblast · Tendon cell

Wandering cell	Mast cell · Macrophage

see also soft tissue

Protein: scleroproteins

Extracellular matrix

Collagen

1-12	type I (COL1A1, COL1A2) · type II (COL2A1) · type III · type IV (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6) · type V (COL5A1, COL5A2, COL5A3) · type VI (COL6A1, COL6A2, COL6A3) · type VII (COL7A1) · type VIII (COL8A1, COL8A2) · type IX (COL9A1, COL9A2, COL9A3) · type X (COL10A1) · type XI (COL11A1, COL11A2) · type XII (COL12A1)

13-29	COL13A1 · COL14A1 · COL15A1 · COL16A1 · COL17A1 · type XVIII (COL18A1, Endostatin) · COL19A1 · COL20A1 · COL21A1 · COL22A1 · COL23A1 · COL24A1 · COL25A1 · COL26A1 · COL27A1 · COL28A1 · COL29A1

Enzymes	Prolyl hydroxylase/Lysyl hydroxylase · Cartilage associated protein/Leprecan · ADAMTS2 · Procollagen peptidase · Lysyl oxidase

Tenascin

Tenascin C · Tenascin X

Laminin

alpha (LAMA1, LAMA2, LAMA3, LAMA4, LAMA5) · beta (LAMB1, LAMB2, LAMB3, LAMB4) · gamma (LAMC1, LAMC2, LAMC3)

Other

ALCAM · Elastin (Tropoelastin) · Vitronectin

Keratin/Cytokeratin

Epithelial keratins (soft alpha-keratins)	type I/chromosome 17 (10, 12, 13, 14, 15, 16, 17, 19, 20) · chromosome 12 (18) · none (21) type II/chromosome 12 (1, 2A, 3, 4, 5, 6A, 6B, 7, 8, 9)

Hair keratins (hard alpha-keratins)	type I/chromosome 17 (31, 32, 33A, 33B, 34, 35, 36, 37, 38) type II/chromosome 12 (81, 82, 83, 84, 85, 86)

Ungrouped alpha	chromosome 17 (23, 24, 25, 26, 27, 28, 39, 40) chromosome 12 (71, 72, 73, 74, 75, 76, 77, 78, 79, 80)

Not alpha	Beta-keratin

Other

Gelatin · Reticulin

see also diseases

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Translations: Collagen

Top

Dansk (Danish)
n. - kollagen

Nederlands (Dutch)
collageen

Français (French)
n. - collagène

Deutsch (German)
n. - Kollagen, Knorpelleim

Ελληνική (Greek)
n. - (χημ.) κολλαγόνο

Italiano (Italian)
collagene

Português (Portuguese)
n. - colágeno (m) (Histol.)

Русский (Russian)
коллаген

Español (Spanish)
n. - colágeno

Svenska (Swedish)
n. - collagen

中文（简体）(Chinese (Simplified))
胶原质

中文（繁體）(Chinese (Traditional))
n. - 膠原質

한국어 (Korean)
n. - 교원질, 콜라겐

日本語 (Japanese)
n. - 膠原

العربيه (Arabic)
‏(الاسم) مولد الغراء في الجسم, كولاجين, مهلمن‏

עברית (Hebrew)
n. - ‮קולגן (פרוטאין)‬

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