Collagen

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Collagen (/ˈkɒlədʒɪn/) is the main structural protein in the extracellular matrix found in the body's various connective tissues. Collagen_sentence_0

As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole-body protein content. Collagen_sentence_1

Collagen consists of amino acids bound together to form a triple helix of elongated fibril known as a collagen helix. Collagen_sentence_2

It is mostly found in connective tissue such as cartilage, bones, tendons, ligaments, and skin. Collagen_sentence_3

Depending upon the degree of mineralization, collagen tissues may be rigid (bone), compliant (tendon), or have a gradient from rigid to compliant (cartilage). Collagen_sentence_4

Collagen is also abundant in corneas, blood vessels, the gut, intervertebral discs, and the dentin in teeth. Collagen_sentence_5

In muscle tissue, it serves as a major component of the endomysium. Collagen_sentence_6

Collagen constitutes one to two percent of muscle tissue and accounts for 6% of the weight of strong, tendinous, muscles. Collagen_sentence_7

The fibroblast is the most common cell that creates collagen. Collagen_sentence_8

Gelatin, which is used in food and industry, is collagen that has been irreversibly hydrolyzed. Collagen_sentence_9

Collagen has many medical uses in treating complications of the bones and skin. Collagen_sentence_10

The name collagen comes from the Greek (kólla), meaning "glue", and suffix -γέν, -gen, denoting "producing". Collagen_sentence_11

This refers to the compound's early use in the process of creating glue from boiling the skin and tendons of horses and other animals. Collagen_sentence_12

Types Collagen_section_0

Over 90% of the collagen in the human body is type I collagen. Collagen_sentence_13

However, as of 2011, 30 types of collagen have been identified, described, and divided into several groups according to the structure they form: All of the types contain at least one triple helix. Collagen_sentence_14

The number of types shows collagen's diverse functionality. Collagen_sentence_15

Collagen_unordered_list_0

  • Fibrillar (Type I, II, III, V, XI)Collagen_item_0_0
  • Non-fibrillarCollagen_item_0_1
    • FACIT (Fibril Associated Collagens with Interrupted Triple Helices) (Type IX, XII, XIV, XIX, XXI)Collagen_item_0_2
    • Short chain (Type VIII, X)Collagen_item_0_3
    • Basement membrane (Type IV)Collagen_item_0_4
    • Multiplexin (Multiple Triple Helix domains with Interruptions) (Type XV, XVIII)Collagen_item_0_5
    • MACIT (Membrane Associated Collagens with Interrupted Triple Helices) (Type XIII, XVII)Collagen_item_0_6
    • Microfibril forming (Type VI)Collagen_item_0_7
    • Anchoring fibrils (Type VII)Collagen_item_0_8

The five most common types are: Collagen_sentence_16

Collagen_unordered_list_1

Medical uses Collagen_section_1

Cardiac applications Collagen_section_2

The collagenous cardiac skeleton which includes the four heart valve rings, is histologically, elastically and uniquely bound to cardiac muscle. Collagen_sentence_17

The cardiac skeleton also includes the separating septa of the heart chambers – the interventricular septum and the atrioventricular septum. Collagen_sentence_18

Collagen contribution to the measure of cardiac performance summarily represents a continuous torsional force opposed to the fluid mechanics of blood pressure emitted from the heart. Collagen_sentence_19

The collagenous structure that divides the upper chambers of the heart from the lower chambers is an impermeable membrane that excludes both blood and electrical impulses through typical physiological means. Collagen_sentence_20

With support from collagen, atrial fibrillation never deteriorates to ventricular fibrillation. Collagen_sentence_21

Collagen is layered in variable densities with smooth muscle mass. Collagen_sentence_22

The mass, distribution, age and density of collagen all contribute to the compliance required to move blood back and forth. Collagen_sentence_23

Individual cardiac valvular leaflets are folded into shape by specialized collagen under variable pressure. Collagen_sentence_24

Gradual calcium deposition within collagen occurs as a natural function of aging. Collagen_sentence_25

Calcified points within collagen matrices show contrast in a moving display of blood and muscle, enabling methods of cardiac imaging technology to arrive at ratios essentially stating blood in (cardiac input) and blood out (cardiac output). Collagen_sentence_26

Pathology of the collagen underpinning of the heart is understood within the category of connective tissue disease. Collagen_sentence_27

Cosmetic surgery Collagen_section_3

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. Collagen_sentence_28

Both human and bovine collagen is widely used as dermal fillers for treatment of wrinkles and skin aging. Collagen_sentence_29

Some points of interest are: Collagen_sentence_30

Collagen_ordered_list_2

  1. 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.Collagen_item_2_14
  2. Most medical collagen is derived from young beef cattle (bovine) from certified BSE-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.Collagen_item_2_15

Bone grafts Collagen_section_4

As the skeleton forms the structure of the body, it is vital that it maintains its strength, even after breaks and injuries. Collagen_sentence_31

Collagen is used in bone grafting as it has a triple helical structure, making it a very strong molecule. Collagen_sentence_32

It is ideal for use in bones, as it does not compromise the structural integrity of the skeleton. Collagen_sentence_33

The triple helical structure of collagen prevents it from being broken down by enzymes, it enables adhesiveness of cells and it is important for the proper assembly of the extracellular matrix. Collagen_sentence_34

Tissue regeneration Collagen_section_5

Collagen scaffolds are used in tissue regeneration, whether in sponges, thin sheets, or gels. Collagen_sentence_35

Collagen has the correct properties for tissue regeneration such as pore structure, permeability, hydrophilicity, and being stable in vivo. Collagen_sentence_36

Collagen scaffolds are also ideal for the deposition of cells such as osteoblasts and fibroblasts, and once inserted, growth is able to continue as normal in the tissue. Collagen_sentence_37

Reconstructive surgical uses Collagen_section_6

Collagens are widely employed in the construction of artificial skin substitutes used in the management of severe burns and wounds. Collagen_sentence_38

These collagens may be derived from bovine, equine, porcine, or even human sources; and are sometimes used in combination with silicones, glycosaminoglycans, fibroblasts, growth factors and other substances. Collagen_sentence_39

Wound healing Collagen_section_7

Collagen is one of the body's key natural resources and a component of skin tissue that can benefit all stages of wound healing. Collagen_sentence_40

When collagen is made available to the wound bed, closure can occur. Collagen_sentence_41

Wound deterioration, followed sometimes by procedures such as amputation, can thus be avoided. Collagen_sentence_42

Collagen is a natural product and is thus used as a natural wound dressing and has properties that artificial wound dressings do not have. Collagen_sentence_43

It is resistant against bacteria, which is of vital importance in a wound dressing. Collagen_sentence_44

It helps to keep the wound sterile, because of its natural ability to fight infection. Collagen_sentence_45

When collagen is used as a burn dressing, healthy granulation tissue is able to form very quickly over the burn, helping it to heal rapidly. Collagen_sentence_46

Throughout the 4 phases of wound healing, collagen performs the following functions in wound healing: Collagen_sentence_47

Collagen_unordered_list_3

  • Guiding function: Collagen fibers serve to guide fibroblasts. Fibroblasts migrate along a connective tissue matrix.Collagen_item_3_16
  • Chemotactic properties: The large surface area available on collagen fibers can attract fibrogenic cells which help in healing.Collagen_item_3_17
  • 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.Collagen_item_3_18
  • Hemostatic properties: Blood platelets interact with the collagen to make a hemostatic plug.Collagen_item_3_19

Basic research Collagen_section_8

Collagen is used in laboratory studies for cell culture, studying cell behavior and cellular interactions with the extracellular environment. Collagen_sentence_48

Chemistry Collagen_section_9

The collagen protein is composed of a triple helix, which generally consists of two identical chains (α1) and an additional chain that differs slightly in its chemical composition (α2). Collagen_sentence_49

The amino acid composition of collagen is atypical for proteins, particularly with respect to its high hydroxyproline content. Collagen_sentence_50

The most common motifs in the amino acid sequence of collagen are glycine-proline-X and glycine-X-hydroxyproline, where X is any amino acid other than glycine, proline or hydroxyproline. Collagen_sentence_51

The average amino acid composition for fish and mammal skin is given. Collagen_sentence_52

Collagen_table_general_0

Amino acidCollagen_header_cell_0_0_0 Abundance in mammal skin

(residues/1000)Collagen_header_cell_0_0_1

Abundance in fish skin

(residues/1000)Collagen_header_cell_0_0_2

GlycineCollagen_cell_0_1_0 329Collagen_cell_0_1_1 339Collagen_cell_0_1_2
ProlineCollagen_cell_0_2_0 126Collagen_cell_0_2_1 108Collagen_cell_0_2_2
AlanineCollagen_cell_0_3_0 109Collagen_cell_0_3_1 114Collagen_cell_0_3_2
HydroxyprolineCollagen_cell_0_4_0 95Collagen_cell_0_4_1 67Collagen_cell_0_4_2
Glutamic acidCollagen_cell_0_5_0 74Collagen_cell_0_5_1 76Collagen_cell_0_5_2
ArginineCollagen_cell_0_6_0 49Collagen_cell_0_6_1 52Collagen_cell_0_6_2
Aspartic acidCollagen_cell_0_7_0 47Collagen_cell_0_7_1 47Collagen_cell_0_7_2
SerineCollagen_cell_0_8_0 36Collagen_cell_0_8_1 46Collagen_cell_0_8_2
LysineCollagen_cell_0_9_0 29Collagen_cell_0_9_1 26Collagen_cell_0_9_2
LeucineCollagen_cell_0_10_0 24Collagen_cell_0_10_1 23Collagen_cell_0_10_2
ValineCollagen_cell_0_11_0 22Collagen_cell_0_11_1 21Collagen_cell_0_11_2
ThreonineCollagen_cell_0_12_0 19Collagen_cell_0_12_1 26Collagen_cell_0_12_2
PhenylalanineCollagen_cell_0_13_0 13Collagen_cell_0_13_1 14Collagen_cell_0_13_2
IsoleucineCollagen_cell_0_14_0 11Collagen_cell_0_14_1 11Collagen_cell_0_14_2
HydroxylysineCollagen_cell_0_15_0 6Collagen_cell_0_15_1 8Collagen_cell_0_15_2
MethionineCollagen_cell_0_16_0 6Collagen_cell_0_16_1 13Collagen_cell_0_16_2
HistidineCollagen_cell_0_17_0 5Collagen_cell_0_17_1 7Collagen_cell_0_17_2
TyrosineCollagen_cell_0_18_0 3Collagen_cell_0_18_1 3Collagen_cell_0_18_2
CysteineCollagen_cell_0_19_0 1Collagen_cell_0_19_1 1Collagen_cell_0_19_2
TryptophanCollagen_cell_0_20_0 0Collagen_cell_0_20_1 0Collagen_cell_0_20_2

Synthesis Collagen_section_10

First, a three-dimensional stranded structure is assembled, with the amino acids glycine and proline as its principal components. Collagen_sentence_53

This is not yet collagen but its precursor, procollagen. Collagen_sentence_54

Procollagen is then modified by the addition of hydroxyl groups to the amino acids proline and lysine. Collagen_sentence_55

This step is important for later glycosylation and the formation of the triple helix structure of collagen. Collagen_sentence_56

Because the hydroxylase enzymes that perform these reactions require vitamin C as a cofactor, a long-term deficiency in this vitamin results in impaired collagen synthesis and scurvy. Collagen_sentence_57

These hydroxylation reactions are catalyzed by two different enzymes: prolyl-4-hydroxylase and lysyl-hydroxylase. Collagen_sentence_58

The reaction consumes one ascorbate molecule per hydroxylation. Collagen_sentence_59

The synthesis of collagen occurs inside and outside of the cell. Collagen_sentence_60

The formation of collagen which results in fibrillary collagen (most common form) is discussed here. Collagen_sentence_61

Meshwork collagen, which is often involved in the formation of filtration systems, is the other form of collagen. Collagen_sentence_62

All types of collagens are triple helices, and the differences lie in the make-up of the alpha peptides created in step 2. Collagen_sentence_63

Collagen_ordered_list_4

  1. Transcription of mRNA: About 44 genes are associated with collagen formation, each coding for a specific mRNA sequence, and typically have the "COL" prefix. The beginning of collagen synthesis begins with turning on genes which are associated with the formation of a particular alpha peptide (typically alpha 1, 2 or 3).Collagen_item_4_20
  2. Pre-pro-peptide formation: Once the final mRNA exits from the cell nucleus and enters into the cytoplasm, it links with the ribosomal subunits and the process of translation occurs. The early/first part of the new peptide is known as the signal sequence. The signal sequence on the N-terminal of the peptide is recognized by a signal recognition particle on the endoplasmic reticulum, which will be responsible for directing the pre-pro-peptide into the endoplasmic reticulum. Therefore, once the synthesis of new peptide is finished, it goes directly into the endoplasmic reticulum for post-translational processing. It is now known as preprocollagen.Collagen_item_4_21
  3. Pre-pro-peptide to pro-collagen: Three modifications of the pre-pro-peptide occur leading to the formation of the alpha peptide:Collagen_item_4_22
    1. The signal peptide on the N-terminal is removed, and the molecule is now known as propeptide (not procollagen).Collagen_item_4_23
    2. Hydroxylation of lysines and prolines on propeptide by the enzymes 'prolyl hydroxylase' and 'lysyl hydroxylase' (to produce hydroxyproline and hydroxylysine) occurs to aid cross-linking of the alpha peptides. This enzymatic step requires vitamin C as a cofactor. In scurvy, the lack of hydroxylation of prolines and lysines causes a looser triple helix (which is formed by three alpha peptides).Collagen_item_4_24
    3. Glycosylation occurs by adding either glucose or galactose monomers onto the hydroxyl groups that were placed onto lysines, but not on prolines.Collagen_item_4_25
    4. Once these modifications have taken place, three of the hydroxylated and glycosylated propeptides twist into a triple helix forming procollagen. Procollagen still has unwound ends, which will be later trimmed. At this point, the procollagen is packaged into a transfer vesicle destined for the Golgi apparatus.Collagen_item_4_26
  4. Golgi apparatus modification: In the Golgi apparatus, the procollagen goes through one last post-translational modification before being secreted out of the cell. In this step, oligosaccharides (not monosaccharides as in step 3) are added, and then the procollagen is packaged into a secretory vesicle destined for the extracellular space.Collagen_item_4_27
  5. Formation of tropocollagen: Once outside the cell, membrane bound enzymes known as collagen peptidases, remove the "loose ends" of the procollagen molecule. What is left is known as tropocollagen. Defects in this step produce one of the many collagenopathies known as Ehlers-Danlos syndrome. This step is absent when synthesizing type III, a type of fibrilar collagen.Collagen_item_4_28
  6. Formation of the collagen fibril: lysyl oxidase, an extracellular copper-dependent enzyme, produces the final step in the collagen synthesis pathway. This enzyme acts on lysines and hydroxylysines producing aldehyde groups, which will eventually undergo covalent bonding between tropocollagen molecules. This polymer of tropocollogen is known as a collagen fibril.Collagen_item_4_29

Amino acids Collagen_section_11

Collagen has an unusual amino acid composition and sequence: Collagen_sentence_64

Collagen_unordered_list_5

  • Glycine is found at almost every third residue.Collagen_item_5_30
  • Proline makes up about 17% of collagen.Collagen_item_5_31
  • 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.Collagen_item_5_32

Cortisol stimulates degradation of (skin) collagen into amino acids. Collagen_sentence_65

Collagen I formation Collagen_section_12

Most collagen forms in a similar manner, but the following process is typical for type I: Collagen_sentence_66

Collagen_ordered_list_6

  1. Inside the cellCollagen_item_6_35
    1. Two types of alpha chains – alpha-1 and alpha 2, are formed during translation on ribosomes along the rough endoplasmic reticulum (RER). These peptide chains known as preprocollagen, have registration peptides on each end and a signal peptide.Collagen_item_6_36
    2. Polypeptide chains are released into the lumen of the RER.Collagen_item_6_37
    3. Signal peptides are cleaved inside the RER and the chains are now known as pro-alpha chains.Collagen_item_6_38
    4. Hydroxylation of lysine and proline amino acids occurs inside the lumen. This process is dependent on and consumes ascorbic acid (vitamin C) as a cofactor.Collagen_item_6_39
    5. Glycosylation of specific hydroxylysine residues occurs.Collagen_item_6_40
    6. Triple alpha helical structure is formed inside the endoplasmic reticulum from two alpha-1 chains and one alpha-2 chain.Collagen_item_6_41
    7. Procollagen is shipped to the Golgi apparatus, where it is packaged and secreted by exocytosis.Collagen_item_6_42
  2. Outside the cellCollagen_item_6_43
    1. Registration peptides are cleaved and tropocollagen is formed by procollagen peptidase.Collagen_item_6_44
    2. 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_item_6_45
    3. Collagen may be attached to cell membranes via several types of protein, including fibronectin, laminin, fibulin and integrin.Collagen_item_6_46

Synthetic pathogenesis Collagen_section_13

Vitamin C deficiency causes scurvy, a serious and painful disease in which defective collagen prevents the formation of strong connective tissue. Collagen_sentence_67

Gums deteriorate and bleed, with loss of teeth; skin discolors, and wounds do not heal. Collagen_sentence_68

Prior to the 18th century, this condition was notorious among long-duration military, particularly naval, expeditions during which participants were deprived of foods containing vitamin C. Collagen_sentence_69

An autoimmune disease such as lupus erythematosus or rheumatoid arthritis may attack healthy collagen fibers. Collagen_sentence_70

Many bacteria and viruses secrete virulence factors, such as the enzyme collagenase, which destroys collagen or interferes with its production. Collagen_sentence_71

Molecular structure Collagen_section_14

A single collagen molecule, tropocollagen, is used to make up larger collagen aggregates, such as fibrils. Collagen_sentence_72

It is approximately 300 nm long and 1.5 nm in diameter, and it is made up of three polypeptide strands (called alpha peptides, see step 2), each of which has the conformation of a left-handed helix – this should not be confused with the right-handed alpha helix. Collagen_sentence_73

These three left-handed helices are twisted together into a right-handed triple helix or "super helix", a cooperative quaternary structure stabilized by many hydrogen bonds. Collagen_sentence_74

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. Collagen_sentence_75

Each microfibril is 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. Collagen_sentence_76

A distinctive feature of collagen is the regular arrangement of amino acids in each of the three chains of these collagen subunits. Collagen_sentence_77

The sequence often follows the pattern Gly-Pro-X or Gly-X-Hyp, where X may be any of various other amino acid residues. Collagen_sentence_78

Proline or hydroxyproline constitute about 1/6 of the total sequence. Collagen_sentence_79

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. Collagen_sentence_80

The high glycine content of collagen is important with respect to stabilization of the collagen helix as this allows the very close association of the collagen fibers within the molecule, facilitating hydrogen bonding and the formation of intermolecular cross-links. Collagen_sentence_81

This kind of regular repetition and high glycine content is found in only a few other fibrous proteins, such as silk fibroin. Collagen_sentence_82

Collagen is not only a structural protein. Collagen_sentence_83

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. Collagen_sentence_84

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. Collagen_sentence_85

Because glycine is the smallest amino acid with no side chain, it plays a unique role in fibrous structural proteins. Collagen_sentence_86

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. Collagen_sentence_87

For the same reason, the rings of the Pro and Hyp must point outward. Collagen_sentence_88

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. Collagen_sentence_89

Lower proline and hydroxyproline contents are characteristic of cold-water, but not warm-water fish; the latter tend to have similar proline and hydroxyproline contents to mammals. Collagen_sentence_90

The lower proline and hydroxproline contents of cold-water fish and other poikilotherm animals leads to their collagen having a lower thermal stability than mammalian collagen. Collagen_sentence_91

This lower thermal stability means that gelatin derived from fish collagen is not suitable for many food and industrial applications. Collagen_sentence_92

The tropocollagen subunits spontaneously self-assemble, with regularly staggered ends, into even larger arrays in the extracellular spaces of tissues. Collagen_sentence_93

Additional assembly of fibrils is guided by fibroblasts, which deposit fully formed fibrils from fibripositors. Collagen_sentence_94

In the fibrillar collagens, molecules are staggered to adjacent molecules by about 67 nm (a unit that is referred to as ‘D’ and changes depending upon the hydration state of the aggregate). Collagen_sentence_95

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". Collagen_sentence_96

These overlap and gap regions are retained as microfibrils assemble into fibrils, and are thus viewable using electron microscopy. Collagen_sentence_97

The triple helical tropocollagens in the microfibrils are arranged in a quasihexagonal packing pattern. Collagen_sentence_98

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). Collagen_sentence_99

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. Collagen_sentence_100

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. Collagen_sentence_101

However, advances in microscopy techniques (i.e. 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. Collagen_sentence_102

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. Collagen_sentence_103

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_sentence_104

Collagen fibrils/aggregates are arranged in different combinations and concentrations in various tissues to provide varying tissue properties. Collagen_sentence_105

In bone, entire collagen triple helices lie in a parallel, staggered array. Collagen_sentence_106

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 hydroxylapatite (approximately) Ca10(OH)2(PO4)6. Collagen_sentence_107

Type I collagen gives bone its tensile strength. Collagen_sentence_108

Associated disorders Collagen_section_15

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. Collagen_sentence_109

Collagen_table_general_1

Genetic defects of collagen genesCollagen_table_caption_1
TypeCollagen_cell_1_0_0 NotesCollagen_cell_1_0_1 Gene(s)Collagen_cell_1_0_2 DisordersCollagen_cell_1_0_3
ICollagen_cell_1_1_0 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, cornea, the endomysium surrounding muscle fibers, fibrocartilage, and the organic part of bones and teeth.Collagen_cell_1_1_1 COL1A1, COL1A2Collagen_cell_1_1_2 Osteogenesis imperfecta, Ehlers–Danlos syndrome, infantile cortical hyperostosis a.k.a. Caffey's diseaseCollagen_cell_1_1_3
IICollagen_cell_1_2_0 Hyaline cartilage, makes up 50% of all cartilage protein. Vitreous humour of the eye.Collagen_cell_1_2_1 COL2A1Collagen_cell_1_2_2 Collagenopathy, types II and XICollagen_cell_1_2_3
IIICollagen_cell_1_3_0 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 uterusCollagen_cell_1_3_1 COL3A1Collagen_cell_1_3_2 Ehlers–Danlos syndrome, Dupuytren's contractureCollagen_cell_1_3_3
IVCollagen_cell_1_4_0 Basal lamina; eye lens. Also serves as part of the filtration system in capillaries and the glomeruli of nephron in the kidney.Collagen_cell_1_4_1 COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6Collagen_cell_1_4_2 Alport syndrome, Goodpasture's syndromeCollagen_cell_1_4_3
VCollagen_cell_1_5_0 Most interstitial tissue, assoc. with type I, associated with placentaCollagen_cell_1_5_1 COL5A1, COL5A2, COL5A3Collagen_cell_1_5_2 Ehlers–Danlos syndrome (classical)Collagen_cell_1_5_3
VICollagen_cell_1_6_0 Most interstitial tissue, assoc. with type ICollagen_cell_1_6_1 COL6A1, COL6A2, COL6A3, COL6A5Collagen_cell_1_6_2 Ulrich myopathy, Bethlem myopathy, atopic dermatitisCollagen_cell_1_6_3
VIICollagen_cell_1_7_0 Forms anchoring fibrils in dermoepidermal junctionsCollagen_cell_1_7_1 COL7A1Collagen_cell_1_7_2 Epidermolysis bullosa dystrophicaCollagen_cell_1_7_3
VIIICollagen_cell_1_8_0 Some endothelial cellsCollagen_cell_1_8_1 COL8A1, COL8A2Collagen_cell_1_8_2 Posterior polymorphous corneal dystrophy 2Collagen_cell_1_8_3
IXCollagen_cell_1_9_0 FACIT collagen, cartilage, assoc. with type II and XI fibrilsCollagen_cell_1_9_1 COL9A1, COL9A2, COL9A3Collagen_cell_1_9_2 EDM2 and EDM3Collagen_cell_1_9_3
XCollagen_cell_1_10_0 Hypertrophic and mineralizing cartilageCollagen_cell_1_10_1 COL10A1Collagen_cell_1_10_2 Schmid metaphyseal dysplasiaCollagen_cell_1_10_3
XICollagen_cell_1_11_0 CartilageCollagen_cell_1_11_1 COL11A1, COL11A2Collagen_cell_1_11_2 Collagenopathy, types II and XICollagen_cell_1_11_3
XIICollagen_cell_1_12_0 FACIT collagen, interacts with type I containing fibrils, decorin and glycosaminoglycansCollagen_cell_1_12_1 COL12A1Collagen_cell_1_12_2 Collagen_cell_1_12_3
XIIICollagen_cell_1_13_0 Transmembrane collagen, interacts with integrin a1b1, fibronectin and components of basement membranes like nidogen and perlecan.Collagen_cell_1_13_1 COL13A1Collagen_cell_1_13_2 Collagen_cell_1_13_3
XIVCollagen_cell_1_14_0 FACIT collagen, also known as undulinCollagen_cell_1_14_1 COL14A1Collagen_cell_1_14_2 Collagen_cell_1_14_3
XVCollagen_cell_1_15_0 Collagen_cell_1_15_1 COL15A1Collagen_cell_1_15_2 Collagen_cell_1_15_3
XVICollagen_cell_1_16_0 Collagen_cell_1_16_1 COL16A1Collagen_cell_1_16_2 Collagen_cell_1_16_3
XVIICollagen_cell_1_17_0 Transmembrane collagen, also known as BP180, a 180 kDa proteinCollagen_cell_1_17_1 COL17A1Collagen_cell_1_17_2 Bullous pemphigoid and certain forms of junctional epidermolysis bullosaCollagen_cell_1_17_3
XVIIICollagen_cell_1_18_0 Source of endostatinCollagen_cell_1_18_1 COL18A1Collagen_cell_1_18_2 Collagen_cell_1_18_3
XIXCollagen_cell_1_19_0 FACIT collagenCollagen_cell_1_19_1 COL19A1Collagen_cell_1_19_2 Collagen_cell_1_19_3
XXCollagen_cell_1_20_0 Collagen_cell_1_20_1 COL20A1Collagen_cell_1_20_2 Collagen_cell_1_20_3
XXICollagen_cell_1_21_0 FACIT collagenCollagen_cell_1_21_1 COL21A1Collagen_cell_1_21_2 Collagen_cell_1_21_3
XXIICollagen_cell_1_22_0 Collagen_cell_1_22_1 COL22A1Collagen_cell_1_22_2 Collagen_cell_1_22_3
XXIIICollagen_cell_1_23_0 MACIT collagenCollagen_cell_1_23_1 COL23A1Collagen_cell_1_23_2 Collagen_cell_1_23_3
XXIVCollagen_cell_1_24_0 Collagen_cell_1_24_1 COL24A1Collagen_cell_1_24_2 Collagen_cell_1_24_3
XXVCollagen_cell_1_25_0 Collagen_cell_1_25_1 COL25A1Collagen_cell_1_25_2 Collagen_cell_1_25_3
XXVICollagen_cell_1_26_0 Collagen_cell_1_26_1 EMID2Collagen_cell_1_26_2 Collagen_cell_1_26_3
XXVIICollagen_cell_1_27_0 Collagen_cell_1_27_1 COL27A1Collagen_cell_1_27_2 Collagen_cell_1_27_3
XXVIIICollagen_cell_1_28_0 Collagen_cell_1_28_1 COL28A1Collagen_cell_1_28_2 Collagen_cell_1_28_3
XXIXCollagen_cell_1_29_0 Epidermal collagenCollagen_cell_1_29_1 COL29A1Collagen_cell_1_29_2 Atopic dermatitisCollagen_cell_1_29_3

In addition to the above-mentioned disorders, excessive deposition of collagen occurs in scleroderma. Collagen_sentence_110

Diseases Collagen_section_16

One thousand mutations have been identified in 12 out of more than 20 types of collagen. Collagen_sentence_111

These mutations can lead to various diseases at the tissue level. Collagen_sentence_112

Osteogenesis imperfecta – Caused by a mutation in type 1 collagen, dominant autosomal disorder, results in weak bones and irregular connective tissue, some cases can be mild while others can be lethal. Collagen_sentence_113

Mild cases have lowered levels of collagen type 1 while severe cases have structural defects in collagen. Collagen_sentence_114

Chondrodysplasias – Skeletal disorder believed to be caused by a mutation in type 2 collagen, further research is being conducted to confirm this. Collagen_sentence_115

Ehlers-Danlos syndrome – Thirteen different types of this disorder, which lead to deformities in connective tissue, are known. Collagen_sentence_116

Some of the rarer types can be lethal, leading to the rupture of arteries. Collagen_sentence_117

Each syndrome is caused by a different mutation. Collagen_sentence_118

For example, the vascular type (vEDS) of this disorder is caused by a mutation in collagen type 3. Collagen_sentence_119

Alport syndrome – Can be passed on genetically, usually as X-linked dominant, but also as both an autosomal dominant and autosomal recessive disorder, sufferers have problems with their kidneys and eyes, loss of hearing can also develop during the childhood or adolescent years. Collagen_sentence_120

Knobloch syndrome – Caused by a mutation in the COL18A1 gene that codes for the production of collagen XVIII. Collagen_sentence_121

Patients present with protrusion of the brain tissue and degeneration of the retina; an individual who has family members suffering from the disorder is at an increased risk of developing it themselves since there is a hereditary link. Collagen_sentence_122

Characteristics Collagen_section_17

Collagen is one of the long, fibrous structural proteins whose functions are quite different from those of globular proteins, such as enzymes. Collagen_sentence_123

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_sentence_124

Collagen has great tensile strength, and is the main component of fascia, cartilage, ligaments, tendons, bone and skin. Collagen_sentence_125

Along with elastin and soft keratin, it is responsible for skin strength and elasticity, and its degradation leads to wrinkles that accompany aging. Collagen_sentence_126

It strengthens blood vessels and plays a role in tissue development. Collagen_sentence_127

It is present in the cornea and lens of the eye in crystalline form. Collagen_sentence_128

It may be one of the most abundant proteins in the fossil record, given that it appears to fossilize frequently, even in bones from the Mesozoic and Paleozoic. Collagen_sentence_129

Uses Collagen_section_18

Collagen has a wide variety of applications, from food to medical. Collagen_sentence_130

For instance, it is used in cosmetic surgery and burn surgery. Collagen_sentence_131

It is widely used in the form of collagen casings for sausages. Collagen_sentence_132

If collagen is subject to sufficient denaturation, 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. Collagen_sentence_133

This process describes the formation of gelatin, which is used in many foods, including flavored gelatin desserts. Collagen_sentence_134

Besides food, gelatin has been used in pharmaceutical, cosmetic, and photography industries. Collagen_sentence_135

It is also used as a dietary supplement. Collagen_sentence_136

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_sentence_137

Collagen adhesive was used by Egyptians about 4,000 years ago, and Native Americans used it in bows about 1,500 years ago. Collagen_sentence_138

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_sentence_139

Collagen normally converts to gelatin, but survived due to dry conditions. Collagen_sentence_140

Animal glues are thermoplastic, softening again upon reheating, 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_sentence_141

Animal sinews and skins, including leather, have been used to make useful articles for millennia. Collagen_sentence_142

Gelatin-resorcinol-formaldehyde glue (and with formaldehyde replaced by less-toxic pentanedial and ethanedial) has been used to repair experimental incisions in rabbit lungs. Collagen_sentence_143

Adaptation and diversification Collagen_section_19

The evolution of collagens was a fundamental step in the early evolution of animals, supporting multicellular animal forms. Collagen_sentence_144

Collagens are the most abundant proteins in vertebrates, making up some 30% of all proteins in the human body. Collagen_sentence_145

Based on their molecular structures, collagen proteins are divided into two main classes – fibril-forming (or fibrillar) collagens and non-fibril-forming (non-fibrillar) collagens – which are further divided into 28 different types (as of 2017), based on individual structures and functions that the protein specifically has in the body. Collagen_sentence_146

Fibrillar collagen, producing the three-dimensional frameworks in different tissues and organs, derived from a single common ancestor during evolution. Collagen_sentence_147

Non-fibrillar collagen is the major supporting component of the extracellular matrix. Collagen_sentence_148

The morphology of fibrillar and non-fibrillar collagen types became differentiated during divergent evolution. Collagen_sentence_149

These two collagen types arose from different mutation and gene duplication events that evolved to the current 28 types of collagen proteins providing the diversification of collagen-supporting structures in the body, such as the skeleton, which formed from the alpha (denoted as α) collagen gene. Collagen_sentence_150

Fibrillar collagen was co-opted during evolutionary adaptation from existing genes by natural selection to construct new organ and tissue structures, enabling the emergence of evolved species with improved capabilities. Collagen_sentence_151

History Collagen_section_20

The molecular and packing structures of collagen have eluded scientists over decades of research. Collagen_sentence_152

The first evidence that it possesses a regular structure at the molecular level was presented in the mid-1930s. Collagen_sentence_153

Since that time, research concentrated on the conformation of the collagen monomer, producing several competing models, although correctly dealing with the conformation of each individual peptide chain. Collagen_sentence_154

The triple-helical "Madras" model provided an accurate model of quaternary structure in collagen. Collagen_sentence_155

This model was supported by further studies showing higher resolution in the late 20th century. Collagen_sentence_156

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. Collagen_sentence_157

As with its monomeric structure, several conflicting models alleged that either the packing arrangement of collagen molecules is 'sheet-like' or microfibrillar. Collagen_sentence_158

The microfibrillar structure of collagen fibrils in tendon, cornea and cartilage was imaged directly by electron microscopy in the late 20th century and early 21st century. Collagen_sentence_159

The microfibrillar structure of tail tendon was modeled as being closest to the observed structure, although it oversimplified the topological progression of neighboring collagen molecules, and so did not predict the correct conformation of the discontinuous D-periodic pentameric arrangement termed microfibril. Collagen_sentence_160

See also Collagen_section_21

Credits to the contents of this page go to the authors of the corresponding Wikipedia page: en.wikipedia.org/wiki/Collagen.