Editing Collagen

{{Short description|Most abundant structural protein in animals}}
{{Use dmy dates|date=January 2021}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
[[Image:Collagentriplehelix.png|thumb|upright=1.5|The triple helix: three left-handed polyproline type II helices (red, green, blue) assemble by an axial hydrogen bond to form a right-handed triple helix, the tertiary structure of collagen.]]

'''Collagen''' ({{IPAc-en|ˈ|k|ɒ|l|ə|dʒ|ə|n}}) is the main structural [[protein]] in the [[extracellular matrix]] of the [[connective tissue]]s of many animals. It is the most abundant protein in mammals,<ref>{{cite journal | vauthors = Shoulders MD, Raines RT | title = Collagen structure and stability | journal = Annual Review of Biochemistry | volume = 78 | pages = 929-958 | date = 2009 | pmid = 19344236 | doi = 10.1146/annurev.biochem.77.032207.120833 | pmc = 2846778 }}</ref> making up 25% to 35% of protein content. [[Amino acid]]s are bound together to form a [[triple helix]] of elongated [[fibril]]<ref>{{Cite news|url=https://www.economist.com/news/science-and-technology/21727059-genetic-engineering-used-make-leather-without-animals-leather-grown-using|title=Leather grown using biotechnology is about to hit the catwalk|newspaper=The Economist|access-date=2 September 2017|url-status=live|archive-url=https://web.archive.org/web/20170901230634/https://www.economist.com/news/science-and-technology/21727059-genetic-engineering-used-make-leather-without-animals-leather-grown-using|archive-date=1 September 2017|date=26 August 2017}}</ref> known as a [[collagen helix]]. It is mostly found in [[cartilage]], [[bone]]s, [[tendon]]s, [[ligament]]s, and [[skin]]. [[Vitamin C]] is vital for collagen synthesis.

Depending on the degree of [[biomineralization|mineralization]], collagen tissues may be rigid (bone) or compliant (tendon) or have a gradient from rigid to compliant (cartilage). Collagen is also abundant in [[cornea]]s, [[blood vessel]]s, the [[Gut (anatomy)|gut]], [[intervertebral disc]]s, and the [[dentin]] in teeth.<ref>Britannica Concise Encyclopedia 2007</ref> In [[muscle tissue]], it serves as a major component of the [[endomysium]]. Collagen constitutes 1% to 2% of muscle tissue and 6% by weight of [[skeletal muscle]].<ref>{{Cite book | vauthors = Sikorski ZE |year=2001 |title=Chemical and Functional Properties of Food Proteins |location=Boca Raton, Florida |publisher=CRC Press |page=242 |isbn=978-1-56676-960-0 }}</ref> The [[fibroblast]] is the most common cell creating collagen in animals. [[Gelatin]], which is used in food and industry, is collagen that was irreversibly [[hydrolyzed]] using heat, basic solutions, or weak acids.<ref>{{Cite journal | vauthors = Bogue RH |title=Conditions Affecting the Hydrolysis of Collagen to Gelatin |journal=Industrial and Engineering Chemistry |volume=15 |issue=11 |pages=1154–59 |year=1923 |doi=10.1021/ie50167a018 }}</ref>

==Etymology==
[[File:Collagen -- Smart-Servier (cropped).jpg|thumb|Collagen]]

The name ''collagen'' comes from the Greek [[wikt:κόλλα#Ancient Greek|κόλλα]] (''kólla''), meaning "[[glue]]", and suffix -γέν, ''-gen'', denoting "producing".<ref>O.E.D. 2nd Edition 2005</ref><ref>{{cite journal | vauthors = Müller WE | title = The origin of metazoan complexity: porifera as integrated animals | journal = Integrative and Comparative Biology | volume = 43 | issue = 1 | pages = 3–10 | date = February 2003 | pmid = 21680404 | doi = 10.1093/icb/43.1.3 | s2cid = 17232196 | citeseerx = 10.1.1.333.3174 }}</ref>

==Types==
As of 2011, 28 types of human collagen have been identified, described, and classified according to their structure.<ref name="Ricard-Blum">{{cite journal | vauthors = Ricard-Blum S | title = The collagen family | journal = Cold Spring Harbor Perspectives in Biology | volume = 3 | issue = 1 | pages = a004978 | date = January 2011 | pmid = 21421911 | pmc = 3003457 | doi = 10.1101/cshperspect.a004978 }}</ref> This diversity shows collagen's diverse functionality.<ref name="Franzke">{{cite journal | vauthors = Franzke CW, Bruckner P, Bruckner-Tuderman L | title = Collagenous transmembrane proteins: recent insights into biology and pathology | journal = Journal of Biological Chemistry | volume = 280 | issue = 6 | pages = 4005–4008 | date = February 2005 | pmid = 15561712 | doi = 10.1074/jbc.R400034200 | doi-access = free }}</ref> All of the types contain at least one [[triple helix]].<ref name="Ricard-Blum" /> Over 90% of the collagen in [[human body|humans]] is [[type I & III collagen]].<ref>Sabiston textbook of surgery board review, 7th edition. Chapter 5 wound healing, question 14</ref>
* Fibrillar (type I, II, III, V, XI)
* Non-fibrillar
** [[FACIT collagen|FACIT]] (fibril-associated collagens with interrupted triple helices) (types IX, XII, XIV, XIX, XXI)
** Short-chain (types VIII, X)
** [[Basement membrane]] (type IV)
** [[Multiplexin]] (multiple triple helix domains with interruptions) (types XV, XVIII)
** MACIT (membrane-associated collagens with interrupted triple helices) (types XIII, XVII)
** Microfibril-forming (type VI)
** [[Anchoring fibrils]] (type VII)

The five most common types are:<ref>{{cite journal | vauthors = Ashokkumar M, Ajayan PM |title=Materials science perspective of multifunctional materials derived from collagen |journal=International Materials Reviews |date=3 April 2021 |volume=66 |issue=3|pages=160–87 |doi=10.1080/09506608.2020.1750807 |bibcode=2021IMRv...66..160A |s2cid=216270520 |url=https://www.tandfonline.com/doi/full/10.1080/09506608.2020.1750807 |issn=0950-6608}}</ref>
* [[Type I collagen|Type I]]: skin, [[tendon]], vasculature, organs, [[bone]] (main component of the organic part of bone)
* [[Type II collagen|Type II]]: [[cartilage]] (main collagenous component of cartilage)
* [[Collagen, type III, alpha 1|Type III]]: reticulate (main component of [[reticular fiber]]s), commonly found alongside type I
* [[Type IV collagen|Type IV]]: forms basal lamina, the epithelium-secreted layer of the [[basement membrane]]
* [[Type-V collagen|Type V]]: cell surfaces, hair, and [[placenta]]

==In humans==
===Cardiac===
The collagenous [[cardiac skeleton]], which includes the four [[heart valve]] rings, is histologically, elastically and uniquely bound to cardiac muscle. The cardiac skeleton also includes the separating [[cardiac septa|septa of the heart chambers]] – the [[interventricular septum]] and the [[atrioventricular septum]]. Collagen contribution to the measure of [[Cardiac stress test|cardiac performance]] summarily represents a continuous torsional force opposed to the [[fluid mechanics]] of blood pressure emitted from the heart. 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. With support from collagen, [[atrial fibrillation]] never deteriorates to [[ventricular fibrillation]]. Collagen is layered in variable densities with smooth muscle mass. The mass, distribution, age, and density of collagen all contribute to the [[compliance (physiology)|compliance]] required to move blood back and forth. Individual cardiac valvular leaflets are folded into shape by specialized collagen under variable [[pressure]]. Gradual [[calcium]] deposition within collagen occurs as a natural function of aging. 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]]). Pathology of the collagen underpinning of the heart is understood within the category of [[connective tissue disease]].{{Citation needed|date=May 2021}}

===Bone grafts===
As the skeleton forms the structure of the body, it is vital that it maintains its strength, even after breaks and injuries. Collagen is used in bone grafting because its triple-helix structure makes it a very strong molecule. It is ideal for use in bones, as it does not compromise the structural integrity of the skeleton. The triple helical structure prevents collagen from being broken down by enzymes, it enables adhesiveness of cells and it is important for the proper assembly of the extracellular matrix.<ref>{{cite journal| vauthors = Cunniffe G, O'Brien F |title=Collagen scaffolds for orthopedic regenerative medicine|journal=The Journal of the Minerals, Metals & Materials Society|year=2011|volume=63|issue=4|pages=66–73|doi=10.1007/s11837-011-0061-y|bibcode = 2011JOM....63d..66C |s2cid=136755815}}</ref>

===Tissue regeneration===
Collagen scaffolds are used in tissue regeneration, whether in sponges,<ref>{{cite journal | vauthors = Geiger M, Li RH, Friess W | title = Collagen sponges for bone regeneration with rhBMP-2 | journal = Advanced Drug Delivery Reviews | volume = 55 | issue = 12 | pages = 1613–1629 | date = November 2003 | pmid = 14623404 | doi = 10.1016/j.addr.2003.08.010 }}</ref> thin sheets,<ref>{{cite journal | vauthors = Bunyaratavej P, Wang HL | title = Collagen membranes: a review | journal = Journal of Periodontology | volume = 72 | issue = 2 | pages = 215–229 | date = February 2001 | pmid = 11288796 | doi = 10.1902/jop.2001.72.2.215 | hdl-access = free | hdl = 2027.42/141506 }}</ref> gels,<ref>{{cite journal | vauthors = Drury JL, Mooney DJ | title = Hydrogels for tissue engineering: scaffold design variables and applications | journal = Biomaterials | volume = 24 | issue = 24 | pages = 4337–4351 | date = November 2003 | pmid = 12922147 | doi = 10.1016/S0142-9612(03)00340-5 }}</ref> or fibers.<ref>{{cite journal | vauthors = Tonndorf R, Aibibu D, Cherif C | title = Collagen multifilament spinning | journal = Materials Science & Engineering. C, Materials for Biological Applications | volume = 106 | pages = 110105 | date = January 2020 | pmid = 31753356 | doi = 10.1016/j.msec.2019.110105 | s2cid = 202227968 }}</ref> Collagen has favorable properties for tissue regeneration, such as pore structure, permeability, hydrophilicity, and stability in vivo. Collagen scaffolds also support deposition of cells, such as [[osteoblasts]] and [[fibroblast]]s, and once inserted, facilitate growth to proceed normally.<ref name=Oliveira>{{cite journal | vauthors = Oliveira SM, Ringshia RA, Legeros RZ, Clark E, Yost MJ, Terracio L, Teixeira CC | title = An improved collagen scaffold for skeletal regeneration | journal = Journal of Biomedical Materials Research. Part A | volume = 94 | issue = 2 | pages = 371–379 | date = August 2010 | pmid = 20186736 | pmc = 2891373 | doi = 10.1002/jbm.a.32694 }}</ref>

===Reconstructive surgery===
Collagens are widely used in the construction of [[artificial skin]] substitutes used for managing severe [[burn (injury)|burns]] and wounds.<ref name="Singh">{{cite journal | vauthors = Singh O, Gupta SS, Soni M, Moses S, Shukla S, Mathur RK | title = Collagen dressing versus conventional dressings in burn and chronic wounds: a retrospective study | journal = Journal of Cutaneous and Aesthetic Surgery | volume = 4 | issue = 1 | pages = 12–16 | date = January 2011 | pmid = 21572675 | pmc = 3081477 | doi = 10.4103/0974-2077.79180 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Gould LJ | title = Topical Collagen-Based Biomaterials for Chronic Wounds: Rationale and Clinical Application | journal = Advances in Wound Care | volume = 5 | issue = 1 | pages = 19–31 | date = January 2016 | pmid = 26858912 | pmc = 4717516 | doi = 10.1089/wound.2014.0595 }}</ref> These collagens may be derived from cow, horse, pig, or even human sources; and are sometimes used in combination with [[silicone]]s, [[glycosaminoglycan]]s, fibroblasts, [[growth factor]]s and other substances.<ref>{{Cite web|title=Collagen and Rosehip Extract Sachet|url=http://alainapharma.com/Collagen%20+%20Rosehip%20Extract.html|url-status=live|access-date=31 May 2021|website=Alaina Pharma|archive-url=https://web.archive.org/web/20160704063720/http://alainapharma.com:80/Collagen%20+%20Rosehip%20Extract.html |archive-date=4 July 2016 }}</ref>

=== Wound healing ===
{{More citations needed section|date=April 2021}}
Collagen is one of the body's key natural resources and a component of skin tissue that can benefit all stages of [[wound healing]].<ref name="scr">{{cite journal | vauthors = Birbrair A, Zhang T, Files DC, Mannava S, Smith T, Wang ZM, Messi ML, Mintz A, Delbono O | title = Type-1 pericytes accumulate after tissue injury and produce collagen in an organ-dependent manner | journal = Stem Cell Research & Therapy | volume = 5 | issue = 6 | pages = 122 | date = November 2014 | pmid = 25376879 | pmc = 4445991 | doi = 10.1186/scrt512 | doi-access = free }}</ref> When collagen is made available to the wound bed, closure can occur. This avoids wound deterioration and procedures such as amputation.

Collagen is used as a natural wound dressing because it has properties that artificial wound dressings do not have. It resists bacteria, which is vitally important in wound dressing. As a burn dressing, collagen helps it heal fast by helping [[granulation tissue]] to grow over the burn.<ref name="Singh"/>

Throughout the four phases of wound healing, collagen performs the following functions:
* Guiding: [[collagen fibers]] guide fibroblasts because they migrate along a connective tissue matrix.
* [[Chemotaxis]]: collagen fibers have a large surface area which attracts fibrogenic cells which help healing.
* [[Nucleation]]: in the presence of certain neutral salt molecules, collagen can act as a nucleating agent causing formation of fibrillar structures.
* [[Antihemorrhagic|Hemostasis]]: Blood [[platelet]]s interact with the collagen to make a hemostatic plug.

==Use in basic research==
Collagen is used in [[basic research|laboratory studies]] for [[cell culture]], studying cell behavior and cellular interactions with the [[extracellular fluid|extracellular environment]].<ref>{{Cite journal | vauthors = Blow N |year=2009 |title=Cell culture: building a better matrix |journal=Nature Methods |volume=6 |issue=8 |pages=619–22 |doi=10.1038/nmeth0809-619 |s2cid=33438539 |doi-access=free }}</ref> Collagen is also widely used as a [[Bio-ink|bioink]] for [[3D bioprinting]] and [[biofabrication]] of 3D tissue models.

==Biology==
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).<ref>{{cite journal | vauthors = Brodsky B, Persikov AV | title = Molecular structure of the collagen triple helix | journal = Advances in Protein Chemistry | volume = 70 | pages = 301–339 | date = 2005-01-01 | pmid = 15837519 | doi = 10.1016/S0065-3233(05)70009-7 | isbn = 978-0120342709 | s2cid = 20879450 }}</ref> The amino acid composition of collagen is atypical for proteins, particularly with respect to its high [[hydroxyproline]] content. The most common motifs in collagen's amino acid sequence are [[glycine]]-[[proline]]-X and glycine-X-hydroxyproline, where X is any amino acid other than glycine, proline or hydroxyproline.

The table below lists average amino acid composition for fish and mammal skin.<ref name="SzpakJAS">{{Cite journal| vauthors = Szpak P |year=2011|title=Fish bone chemistry and ultrastructure: implications for taphonomy and stable isotope analysis|journal=Journal of Archaeological Science|volume=38|issue=12|pages=3358–72|doi=10.1016/j.jas.2011.07.022|bibcode=2011JArSc..38.3358S }}</ref>

{| class="wikitable sortable"
|-
! Amino acid !! Abundance in mammal skin<br>([[Residue (biochemistry)|residues]]/1000) !! Abundance in fish skin<br>(residues/1000)
|-
| [[Glycine]] || 329 || 339
|-
| [[Proline]] || 126 || 108
|-
| [[Alanine]] || 109 || 114
|-
| [[Hydroxyproline]] || 95 || 67
|-
| [[Glutamic acid]] || 74 || 76
|-
| [[Arginine]] || 49 || 52
|-
| [[Aspartic acid]] || 47 || 47
|-
| [[Serine]] || 36 || 46
|-
| [[Lysine]] || 29 || 26
|-
| [[Leucine]] || 24 || 23
|-
| [[Valine]] || 22 || 21
|-
| [[Threonine]] || 19 || 26
|-
| [[Phenylalanine]] || 13 || 14
|-
| [[Isoleucine]] || 11 || 11
|-
| [[Hydroxylysine]] || 6 || 8
|-
| [[Methionine]] || 6 || 13
|-
| [[Histidine]] || 5 || 7
|-
| [[Tyrosine]] || 3 || 3
|-
| [[Cysteine]] || 1 || 1
|-
| [[Tryptophan]] || 0 || 0
|}

==Synthesis==
{{More citations needed section|date=April 2021}}
First, a three-dimensional stranded structure is assembled, mostly composed of the amino acids glycine and proline. This is the collagen precursor procollagen. Then, procollagen is modified by the addition of [[hydroxyl]] groups to the amino acids proline and [[lysine]]. This step is important for later [[glycosylation]] and the formation of collagen's triple helix structure. Because the [[hydroxylase]] enzymes performing these reactions require [[vitamin C]] as a [[Cofactor (biochemistry)|cofactor]], a long-term deficiency in this vitamin results in impaired collagen synthesis and [[scurvy]].<ref>{{cite journal | vauthors = Peterkofsky B | title = Ascorbate requirement for hydroxylation and secretion of procollagen: relationship to inhibition of collagen synthesis in scurvy | journal = The American Journal of Clinical Nutrition | volume = 54 | issue = 6 Suppl | pages = 1135S–1140S | date = December 1991 | pmid = 1720597 | doi = 10.1093/ajcn/54.6.1135s | doi-access = free }}</ref> These hydroxylation reactions are catalyzed by the enzymes [[prolyl 4-hydroxylase]]<ref>{{cite journal | vauthors = Gorres KL, Raines RT | title = Prolyl 4-hydroxylase | journal = Critical Reviews in Biochemistry and Molecular Biology | volume = 45 | issue = 2 | pages = 106–124 | date = April 2010 | pmid = 20199358 | pmc = 2841224 | doi = 10.3109/10409231003627991 }}</ref> and [[lysyl hydroxylase]]. The reaction consumes one ascorbate molecule per hydroxylation.<ref>{{cite journal | vauthors = Myllylä R, Majamaa K, Günzler V, Hanauske-Abel HM, Kivirikko KI | title = Ascorbate is consumed stoichiometrically in the uncoupled reactions catalyzed by prolyl 4-hydroxylase and lysyl hydroxylase | journal = The Journal of Biological Chemistry | volume = 259 | issue = 9 | pages = 5403–5405 | date = May 1984 | pmid = 6325436 | doi = 10.1016/S0021-9258(18)91023-9 | doi-access = free }}</ref> Collagen synthesis occurs inside and outside cells. 

The most common form of collagen is fibrillary collagen. Another common form is meshwork collagen, which is often involved in the formation of filtration systems. All types of collagen are triple helices, but differ in the make-up of their alpha peptides created in step 2. Below we discuss the formation of fibrillary collagen.
# '''Transcription of mRNA''': Synthesis begins with turning on genes associated with the formation of a particular alpha peptide (typically alpha 1, 2 or 3). About 44 genes are associated with collagen formation, each coding for a specific mRNA sequence, and are typically named with the "''COL''" prefix.
# '''Pre-pro-peptide formation''': The created mRNA exits the cell nucleus into the cytoplasm. There, it links with the ribosomal subunits and is translated into a peptide. The peptide goes into the endoplasmic reticulum for post-translational processing. It is directed there by a [[signal recognition particle]] on the [[endoplasmic reticulum]], which recognizes the peptide's {{Nowrap|[[N-terminal]]}} signal sequence (the early part of the sequence). The processed product is a [[Protein precursor|pre-pro-peptide]] called preprocollagen.
# '''Pro-collagen''' '''formation''': Three modifications of the pre-pro-peptide form the alpha peptide:
## The signal peptide on the N-terminal is removed. The molecule is now called ''propeptide.''
## Lysines and prolines are hydroxylated by the enzymes 'prolyl hydroxylase' and 'lysyl hydroxylase', producing hydroxyproline and hydroxylysine. This helps in cross-linking 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).
## Glycosylation occurs by adding either glucose or galactose monomers onto the hydroxyl groups that were placed onto lysines, but not on prolines.
## Three of the hydroxylated and glycosylated propeptides twist into a triple helix (except for its ends), forming procollagen. It is packaged into a transfer vesicle destined for the Golgi apparatus.
# '''Modification''' '''and secretion''': In the [[Golgi apparatus]], the procollagen goes through one last post-translational modification, adding oligosaccharides (not monosaccharides as in step 3). Then it is packaged into a secretory vesicle to be secreted from the cell.
# '''Tropocollagen''' '''formation''': Outside the cell, membrane-bound enzymes called collagen peptidases remove the unwound ends of the molecule, producing tropocollagen. Defects in this step produce various collagenopathies called [[Ehlers–Danlos syndrome]]. This step is absent when synthesizing type III, a type of fibrillar collagen.
# '''Collagen fibril formation''': [[Lysyl oxidase]], a [[Copper in health|copper-dependent]] enzyme, acts on lysines and hydroxylysines, producing aldehyde groups, which eventually form covalent bonds between tropocollagen molecules. This polymer of tropocollagen is called a collagen fibril.

[[File:Tropocollagen cross-linkage lysyl oxidase (EN).svg|thumb|upright=1.3|Action of [[lysyl oxidase]]]]

===Amino acids===
Collagen has an unusual amino acid composition and sequence:
* Glycine is found at almost every third [[residue (biochemistry)|residue]].
* Proline makes up about 17% of collagen.
* Collagen contains two unusual derivative amino acids not directly inserted during [[translation (genetics)|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]] derived from proline
** [[Hydroxylysine]] derived from lysine – depending on the type of collagen, varying numbers of hydroxylysines are [[glycosylation|glycosylated]] (mostly having [[disaccharide]]s attached).

[[Cortisol]] stimulates [[Amide hydrolysis|degradation]] of (skin) collagen into amino acids.<ref>{{cite journal | vauthors = Houck JC, Sharma VK, Patel YM, Gladner JA | title = Induction of collagenolytic and proteolytic activities by anti-inflammatory drugs in the skin and fibroblast | journal = Biochemical Pharmacology | volume = 17 | issue = 10 | pages = 2081–2090 | date = October 1968 | pmid = 4301453 | doi = 10.1016/0006-2952(68)90182-2 }}</ref>

=== 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 alpha chains – alpha-1 and alpha 2, are formed during [[translation (genetics)|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]].<ref name="Dict">{{cite web |title=preprocollagen |url=https://medical-dictionary.thefreedictionary.com/preprocollagen |website=The Free Dictionary}}</ref>
## 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 and consumes [[ascorbic acid]] (vitamin C) as a [[cofactor (biochemistry)|cofactor]].
## [[Glycosylation]] of specific hydroxylysine residues occurs.
## Triple alpha helical structure is formed inside the endoplasmic reticulum from two alpha-1 chains and one alpha-2 chain.
## [[Procollagen]] is shipped to the [[Golgi apparatus]], where it is packaged and secreted into the extracellular space 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]], [[laminin]], [[fibulin]], and [[integrin]].

==Molecular structure==
{{More citations needed section|date=April 2021}}
A single collagen molecule, tropocollagen, is used to make up larger collagen aggregates, such as fibrils. It is approximately 300&nbsp;[[nanometre|nm]] long and 1.5&nbsp;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]]. 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 bond]]s. 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 [[wikt:interdigitate|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.

[[File:Collagen biosynthesis (en).png|thumb|upright=1.3|Three [[polypeptide]]s coil to form tropocollagen. Many tropocollagens then bind together to form a fibril, and many of these then form a fibre.]]

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 [[glycine|Gly]]-[[proline|Pro]]-X or Gly-X-[[hydroxyproline|Hyp]], where X may be any of various other amino acid residues.<ref name="SzpakJAS"/> 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 GX<sub>1</sub>X<sub>2</sub> character of collagen alpha-peptides. 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.<ref name="SzpakJAS"/> This kind of regular repetition and high glycine content is found in only a few other fibrous proteins, such as silk [[fibroin]].

Collagen is not only 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 because of a stereoelectronic effect;<ref>{{cite journal | vauthors = Holmgren SK, Taylor KM, Bretscher LE, Raines RT | title = Code for collagen stability deciphered | journal = Nature | volume = 392 | pages = 666-667 | date = 1998 | pmid = 9565027 | doi = 10.1038/33573 }}</ref> a lower concentration of them is required in animals such as fish, whose [[thermoregulation|body temperatures]] are lower than most warm-blooded animals. 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.<ref name="SzpakJAS"/> The lower proline and hydroxyproline contents of cold-water fish and other [[poikilothermic|poikilotherm]] animals lead to their collagen having a lower thermal stability than mammalian collagen.<ref name="SzpakJAS"/> This lower thermal stability means that [[gelatin]] derived from fish collagen is not suitable for many food and industrial applications.

The tropocollagen [[protein subunit|subunits]] spontaneously [[molecular self-assembly|self-assemble]], with regularly staggered ends, into even larger arrays in the [[extracellular]] spaces of tissues.<ref>{{cite journal | vauthors = Hulmes DJ | title = Building collagen molecules, fibrils, and suprafibrillar structures | journal = Journal of Structural Biology | volume = 137 | issue = 1–2 | pages = 2–10 | year = 2002 | pmid = 12064927 | doi = 10.1006/jsbi.2002.4450 }}</ref><ref name="Hulmes, D.J. 1992. p. 49">{{cite journal | vauthors = Hulmes DJ | title = The collagen superfamily--diverse structures and assemblies | journal = Essays in Biochemistry | volume = 27 | pages = 49–67 | year = 1992 | pmid = 1425603 }}</ref> Additional assembly of fibrils is guided by fibroblasts, which deposit fully formed fibrils from fibripositors. In the fibrillar collagens, molecules are staggered to adjacent molecules by about 67&nbsp;[[Nanometre|nm]] (a unit that is referred to as 'D' and changes depending upon the hydration state of the aggregate). 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".<ref name="Orgel" /> These overlap and gap regions are retained as microfibrils assemble into fibrils, and are thus viewable using electron microscopy. The triple helical tropocollagens in the microfibrils are arranged in a quasihexagonal packing pattern.<ref name="Orgel" /><ref name="Hulmes Miller 1979" />
[[File:Collagen fibrils in rabbit skin.jpg|thumb|upright|The D-period of collagen fibrils results in visible 67nm bands when observed by electron microscopy.]]
There is some [[covalent bond|covalent]] crosslinking within the triple helices and a variable amount of covalent crosslinking between tropocollagen helices forming well-organized aggregates (such as fibrils).<ref>{{cite journal | vauthors = Perumal S, Antipova O, Orgel JP | title = Collagen fibril architecture, domain organization, and triple-helical conformation govern its proteolysis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 8 | pages = 2824–2829 | date = February 2008 | pmid = 18287018 | pmc = 2268544 | doi = 10.1073/pnas.0710588105 | doi-access = free | bibcode = 2008PNAS..105.2824P }}</ref> 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.<ref name="Hulmes, D.J. 1992. p. 49"/> Collagen's [[soluble|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 [[cross-link|crosslinked]]. 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''.<ref>{{Cite journal| vauthors = Buchanan JK, Zhang Y, Holmes G, Covington AD, Prabakar S |date=2019|title=Role of X-ray Scattering Techniques in Understanding the Collagen Structure of Leather|journal=ChemistrySelect|language=en|volume=4|issue=48|pages=14091–102|doi=10.1002/slct.201902908|s2cid=212830367|issn=2365-6549|url=http://nectar.northampton.ac.uk/15330/1/Role_Xray_Scattering_Leather_Covington_etel_2019.pdf |archive-url=https://web.archive.org/web/20220127190335/http://nectar.northampton.ac.uk/15330/1/Role_Xray_Scattering_Leather_Covington_etel_2019.pdf |archive-date=2022-01-27 |url-status=live}}</ref> 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.<ref>{{cite journal | vauthors = Sweeney SM, Orgel JP, Fertala A, McAuliffe JD, Turner KR, Di Lullo GA, Chen S, Antipova O, Perumal S, Ala-Kokko L, Forlino A, Cabral WA, Barnes AM, Marini JC, San Antonio JD | title = Candidate cell and matrix interaction domains on the collagen fibril, the predominant protein of vertebrates | journal = The Journal of Biological Chemistry | volume = 283 | issue = 30 | pages = 21187–21197 | date = July 2008 | pmid = 18487200 | pmc = 2475701 | doi = 10.1074/jbc.M709319200 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Twardowski T, Fertala A, Orgel JP, San Antonio JD | title = Type I collagen and collagen mimetics as angiogenesis promoting superpolymers | journal = Current Pharmaceutical Design | volume = 13 | issue = 35 | pages = 3608–3621 | year = 2007 | pmid = 18220798 | doi = 10.2174/138161207782794176 }}</ref> 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.<ref>{{cite journal | vauthors = Minary-Jolandan M, Yu MF | title = Nanomechanical heterogeneity in the gap and overlap regions of type I collagen fibrils with implications for bone heterogeneity | journal = Biomacromolecules | volume = 10 | issue = 9 | pages = 2565–2570 | date = September 2009 | pmid = 19694448 | doi = 10.1021/bm900519v }}</ref>

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&nbsp;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) Ca<sub>10</sub>(OH)<sub>2</sub>(PO<sub>4</sub>)<sub>6</sub>.<ref>Ross, M. H. and Pawlina, W. (2011) ''Histology'', 6th ed., Lippincott Williams & Wilkins, p. 218.</ref> Type I collagen gives bone its [[tensile strength]].

==Associated disorders==

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

{| class="wikitable"
|-
|+'''Genetic defects of collagen genes'''

| '''Type''' || '''Notes''' || '''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 [[healing|heals]] by repair. It is found in [[tendon]]s, skin, artery walls, cornea, the [[endomysium]] surrounding muscle fibers, fibrocartilage, and the organic part of bones and teeth. || [[COL1A1]], [[COL1A2]] || [[Osteogenesis imperfecta]], [[Ehlers–Danlos syndrome]], [[infantile cortical hyperostosis]] a.k.a. Caffey's disease
 |-
 | [[Type-II collagen|II]] || [[Hyaline cartilage]], makes up 50% of all cartilage protein. [[Vitreous humour]] of the eye. || [[COL2A1]] || [[Collagenopathy, types II and XI]]
 |-
 | [[Type-III collagen|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]]
 |-
 | [[Type-IV collagen|IV]] || [[Basal lamina]]; [[eye lens]]. Also serves as part of the filtration system in [[capillaries]] and the [[Glomerulus (kidney)|glomeruli]] of [[nephron]] in the [[kidney]]. || [[Collagen, type IV, alpha 1|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]], [[COL6A5]] || [[Ulrich myopathy]], [[Bethlem myopathy]], [[atopic dermatitis]]<ref>{{cite journal | vauthors = Söderhäll C, Marenholz I, Kerscher T, Rüschendorf F, Esparza-Gordillo J, Worm M, Gruber C, Mayr G, Albrecht M, Rohde K, Schulz H, Wahn U, Hubner N, Lee YA | title = Variants in a novel epidermal collagen gene (COL29A1) are associated with atopic dermatitis | journal = PLOS Biology | volume = 5 | issue = 9 | pages = e242 | date = September 2007 | pmid = 17850181 | pmc = 1971127 | doi = 10.1371/journal.pbio.0050242 | doi-access = free }}</ref>
 |-
 | VII || Forms [[anchoring fibril]]s in [[dermoepidermal junction]]s || [[COL7A1]] || [[Epidermolysis bullosa dystrophica]]
 |-
 | VIII || Some [[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 [[Mineralization (biology)|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]], also known as undulin || [[COL14A1]] || –
 |-
 | XV || – || [[COL15A1]] || –
 |-
 | XVI || [[FACIT collagen]] || [[COL16A1]] || –
 |-
 | [[Collagen XVII|XVII]] || Transmembrane collagen, also known as BP180, a 180 kDa protein || [[COL17A1]] || [[Bullous pemphigoid]] and certain forms of junctional [[epidermolysis bullosa]]
 |-
 | [[Type XVIII collagen|XVIII]] || Source of [[endostatin]] || [[COL18A1]] || –
 |-
 | XIX || [[FACIT collagen]] || [[COL19A1]] || –
 |-
 | XX || – || [[COL20A1]] || –
 |-
 | XXI || [[FACIT collagen]] || [[COL21A1]] || –
 |-
 | XXII || [[FACIT collagen]] || [[COL22A1]] || –
 |-
 | [[Collagen, type XXIII, alpha 1|XXIII]] || MACIT collagen || [[COL23A1]] || –
 |-
 | XXIV || – || [[COL24A1]] || –
 |-
 | XXV || – || [[COL25A1]] || –
 |-
 | XXVI || – || [[EMID2]] || –
 |-
 | XXVII || – || [[COL27A1]] || –
 |-
 | XXVIII || – || [[COL28A1]] || –
  |-
 | XXIX || – || [[COL29A1]] || –
|}

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

==Diseases==
One thousand mutations have been identified in 12 out of more than 20 types of collagen. These mutations can lead to various diseases at the tissue level.<ref name="Mahajan, VB 2010">{{cite journal | vauthors = Mahajan VB, Olney AH, Garrett P, Chary A, Dragan E, Lerner G, Murray J, Bassuk AG | title = Collagen XVIII mutation in Knobloch syndrome with acute lymphoblastic leukemia | journal = American Journal of Medical Genetics. Part A | volume = 152A | issue = 11 | pages = 2875–2879 | date = November 2010 | pmid = 20799329 | pmc = 2965270 | doi = 10.1002/ajmg.a.33621 }}</ref>

[[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. Mild cases have lowered levels of collagen type 1 while severe cases have structural defects in collagen.<ref>{{cite journal | vauthors = Gajko-Galicka A | title = Mutations in type I collagen genes resulting in osteogenesis imperfecta in humans | journal = Acta Biochimica Polonica | volume = 49 | issue = 2 | pages = 433–441 | year = 2002 | pmid = 12362985 | doi = 10.18388/abp.2002_3802 | url = http://www.actabp.pl/pdf/2_2002/433-441.pdf | url-status = live | doi-access = free | archive-url = https://web.archive.org/web/20130607085009/http://www.actabp.pl/pdf/2_2002/433-441.pdf | archive-date = 7 June 2013 }}</ref>

[[Chondrodysplasia]]s – Skeletal disorder believed to be caused by a mutation in ''type 2 collagen'', further research is being conducted to confirm this.<ref name="pmid2624272">{{cite journal | vauthors = Horton WA, Campbell D, Machado MA, Chou J | title = Type II collagen screening in the human chondrodysplasias | journal = American Journal of Medical Genetics | volume = 34 | issue = 4 | pages = 579–583 | date = December 1989 | pmid = 2624272 | doi = 10.1002/ajmg.1320340425 }}</ref>

[[Ehlers–Danlos syndrome]] – Thirteen different types of this disorder, which lead to deformities in connective tissue, are known.<ref>{{cite journal | vauthors = Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, Bloom L, Bowen JM, Brady AF, Burrows NP, Castori M, Cohen H, Colombi M, Demirdas S, De Backer J, De Paepe A, Fournel-Gigleux S, Frank M, Ghali N, Giunta C, Grahame R, Hakim A, Jeunemaitre X, Johnson D, Juul-Kristensen B, Kapferer-Seebacher I, Kazkaz H, Kosho T, Lavallee ME, Levy H, Mendoza-Londono R, Pepin M, Pope FM, Reinstein E, Robert L, Rohrbach M, Sanders L, Sobey GJ, Van Damme T, Vandersteen A, van Mourik C, Voermans N, Wheeldon N, Zschocke J, Tinkle B | title = The 2017 international classification of the Ehlers-Danlos syndromes | journal = American Journal of Medical Genetics. Part C, Seminars in Medical Genetics | volume = 175 | issue = 1 | pages = 8–26 | date = March 2017 | pmid = 28306229 | doi = 10.1002/ajmg.c.31552 | s2cid = 4440499 | doi-access = free }}</ref> Some of the rarer types can be lethal, leading to the rupture of arteries. Each syndrome is caused by a different mutation. For example, the vascular type (vEDS) of this disorder is caused by a mutation in ''collagen type 3''.<ref name=Hamel>{{cite journal | vauthors = Hamel BC, Pals G, Engels CH, van den Akker E, Boers GH, van Dongen PW, Steijlen PM | title = Ehlers-Danlos syndrome and type III collagen abnormalities: a variable clinical spectrum | journal = Clinical Genetics | volume = 53 | issue = 6 | pages = 440–446 | date = June 1998 | pmid = 9712532 | doi = 10.1111/j.1399-0004.1998.tb02592.x | s2cid = 39089732 }}</ref>

[[Alport syndrome]] – Can be passed on genetically, usually as X-linked dominant, but also as both an autosomal dominant and autosomal recessive disorder, those with the condition have problems with their kidneys and eyes, loss of hearing can also develop during the childhood or adolescent years.<ref>{{cite book | vauthors = Kashtan CE |year=1993 |volume=Collagen IV-Related Nephropathies |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK1207/ |chapter=Alport Syndrome and Thin Basement Membrane Nephropathy | veditors = Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP |title=GeneReviews |publisher=University of Washington, Seattle |location=Seattle WA |pmid=20301386}}</ref>

[[Knobloch syndrome]] – Caused by a mutation in the [[COL18A1]] gene that codes for the production of collagen XVIII. Patients present with protrusion of the brain tissue and degeneration of the retina; an individual who has family members with the disorder is at an increased risk of developing it themselves since there is a hereditary link.<ref name="Mahajan, VB 2010"/>

==Animal harvesting==
When not synthesized, collagen can be harvested from animal skin. This has led to deforestation as has occurred in Paraguay where large collagen producers buy large amounts of cattle hides from regions that have been [[Clearcutting|clear-cut]] for cattle grazing.<ref>{{Cite web |last=Alexander |first=Iñigo |date=2024-10-09 |title=Collagen and meat giants fuel deforestation and rights violations in Paraguay: Report |url=https://news.mongabay.com/2024/10/collagen-and-cattle-fuel-deforestation-and-rights-violations-in-paraguay-says-new-report/ |access-date=2024-10-09 |website=Mongabay Environmental News |language=en-US}}</ref>

==Characteristics==
Collagen is one of the long, [[fibrous protein|fibrous structural proteins]] whose functions are quite different from those of [[globular protein]]s, such as [[enzyme]]s. 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]], [[ligament]]s, [[tendon]]s, [[bone]] and skin.<ref>{{Cite book | vauthors = Fratzl P |title=Collagen: Structure and Mechanics |publisher=Springer |location=New York |year=2008 |isbn=978-0-387-73905-2 }}</ref><ref>{{cite journal | vauthors = Buehler MJ | title = Nature designs tough collagen: explaining the nanostructure of collagen fibrils | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 33 | pages = 12285–12290 | date = August 2006 | pmid = 16895989 | pmc = 1567872 | doi = 10.1073/pnas.0603216103 | doi-access = free | bibcode = 2006PNAS..10312285B }}</ref> Along with [[elastin]] and soft [[keratin]], it is responsible for skin strength and elasticity, and its degradation leads to [[wrinkle]]s that accompany [[aging]].<ref name="pharmax2">[http://pharmaxchange.info/press/2011/03/the-ageing-skin-part-4e-dermal-fillers/ Dermal Fillers | The Ageing Skin] {{webarchive|url=https://web.archive.org/web/20110513225727/http://pharmaxchange.info/press/2011/03/the-ageing-skin-part-4e-dermal-fillers/ |date=13 May 2011 }}. Pharmaxchange.info. Retrieved on 21 April 2013.</ref> It strengthens [[blood vessel]]s and plays a role in [[biological tissue|tissue]] development. It is present in the [[cornea]] and lens of the eye in [[crystal]]line form. 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]].<ref name=ZL11>{{cite journal| vauthors = Zylberberg L, Laurin M |year=2011 |title=Analysis of fossil bone organic matrix by transmission electron microscopy |journal=Comptes Rendus Palevol |volume=11 |issue=5–6 |pages=357–66 | doi = 10.1016/j.crpv.2011.04.004}}</ref>

=== Mechanical properties ===
Collagen is a complex hierarchical material with [[mechanical properties]] that vary significantly across different scales.

On the molecular scale, [[Molecular dynamics|atomistic]] and [[Coarse-grained modeling|course-grained modeling]] simulations, as well as numerous experimental methods, have led to several estimates of the [[Young's modulus]] of collagen at the molecular level. Only above a certain strain rate is there a strong relationship between elastic modulus and strain rate, possibly due to the large number of atoms in a collagen molecule.<ref name=":0">{{cite journal | vauthors = Gautieri A, Vesentini S, Redaelli A, Buehler MJ | title = Hierarchical structure and nanomechanics of collagen microfibrils from the atomistic scale up | journal = Nano Letters | volume = 11 | issue = 2 | pages = 757–766 | date = February 2011 | pmid = 21207932 | doi = 10.1021/nl103943u | bibcode = 2011NanoL..11..757G | hdl = 1721.1/77587 | hdl-access = free }}</ref> The length of the molecule is also important, where longer molecules have lower tensile strengths than shorter ones due to short molecules having a large proportion of hydrogen bonds being broken and reformed.<ref>{{Cite journal | vauthors = Pradhan SM, Katti DR, Katti KS |title=Steered Molecular Dynamics Study of Mechanical Response of Full Length and Short Collagen Molecules |journal=Journal of Nanomechanics and Micromechanics |date=2011 |language=en |volume=1 |issue=3 |pages=104–110 |doi=10.1061/(ASCE)NM.2153-5477.0000035 |issn=2153-5434}}</ref>

On the [[fibril]]lar scale, collagen has a lower modulus compared to the molecular scale, and varies depending on geometry, scale of observation, deformation state, and hydration level.<ref name=":0" /> By increasing the [[Cross-link|crosslink density]] from zero to 3 per molecule, the maximum stress the fibril can support increases from 0.5 GPa to 6 GPa.<ref>{{cite journal | vauthors = Buehler MJ | title = Nanomechanics of collagen fibrils under varying cross-link densities: atomistic and continuum studies | journal = Journal of the Mechanical Behavior of Biomedical Materials | volume = 1 | issue = 1 | pages = 59–67 | date = January 2008 | pmid = 19627772 | doi = 10.1016/j.jmbbm.2007.04.001 }}</ref>

Limited tests have been done on the tensile strength of the collagen fiber, but generally it has been shown to have a lower Young's modulus compared to fibrils.<ref>{{cite journal | vauthors = Gentleman E, Lay AN, Dickerson DA, Nauman EA, Livesay GA, Dee KC | title = Mechanical characterization of collagen fibers and scaffolds for tissue engineering | journal = Biomaterials | volume = 24 | issue = 21 | pages = 3805–3813 | date = September 2003 | pmid = 12818553 | doi = 10.1016/s0142-9612(03)00206-0 }}</ref>

When studying the mechanical properties of collagen, [[tendon]] is often chosen as the ideal material because it is close to a pure and aligned collagen structure. However, at the macro, tissue scale, the vast number of structures that collagen fibers and fibrils can be arranged into results in highly variable properties. For example, tendon has primarily parallel fibers, whereas skin consists of a net of wavy fibers, resulting in a much higher strength and lower ductility in tendon compared to skin. The mechanical properties of collagen at multiple hierarchical levels is given.
{| class="wikitable"
|+Young's Modulus of Collagen at Multiple Hierarchical Levels
!Hierarchical Level
!Young's Modulus
|-
|Molecular (via atomistic modeling)
|2.4-7 GPa<ref>{{cite journal | vauthors = Vesentini S, Fitié CF, Montevecchi FM, Redaelli A | title = Molecular assessment of the elastic properties of collagen-like homotrimer sequences | journal = Biomechanics and Modeling in Mechanobiology | volume = 3 | issue = 4 | pages = 224–234 | date = June 2005 | pmid = 15824897 | doi = 10.1007/s10237-004-0064-5 }}</ref><ref>{{Cite journal | vauthors = Buehler MJ | date = August 2006 |title=Atomistic and continuum modeling of mechanical properties of collagen: Elasticity, fracture, and self-assembly |journal=Journal of Materials Research |language=en |volume=21 |issue=8 |pages=1947–1961 |doi=10.1557/jmr.2006.0236 | bibcode = 2006JMatR..21.1947B |issn=2044-5326}}</ref>
|-
|Fibril
|0.2-0.8 GPa<ref>{{cite journal | vauthors = van der Rijt JA, van der Werf KO, Bennink ML, Dijkstra PJ, Feijen J | title = Micromechanical testing of individual collagen fibrils | journal = Macromolecular Bioscience | volume = 6 | issue = 9 | pages = 697–702 | date = September 2006 | pmid = 16967482 | doi = 10.1002/mabi.200600063 }}</ref>
|-
|Fiber (measured from cross-linked rat tail tendon)
|1.10 GPa<ref name=":1">{{cite journal | vauthors = Gentleman E, Lay AN, Dickerson DA, Nauman EA, Livesay GA, Dee KC | title = Mechanical characterization of collagen fibers and scaffolds for tissue engineering | journal = Biomaterials | volume = 24 | issue = 21 | pages = 3805–3813 | date = September 2003 | pmid = 12818553 | doi = 10.1016/S0142-9612(03)00206-0 }}</ref>
|-
|Fiber (measured from non-cross-linked rat tail tendon)
|50-250 MPa<ref name=":1" />
|}
Collagen is known to be a viscoelastic solid. When the collagen fiber is modeled as two Kelvin-Voigt models in series, each consisting of a spring and a dashpot in parallel, the strain in the fiber can be modeled according to the following equation:

<math>\frac{d\epsilon_D}{d\epsilon_T}=\alpha + (\beta - \alpha) exp[-\gamma\frac{\epsilon_T}{\dot{\epsilon_T}}]</math>

where α, β, and γ are defined materials properties, ε<sub>D</sub> is fibrillar strain, and ε<sub>T</sub> is total strain.<ref>{{cite journal | vauthors = Puxkandl R, Zizak I, Paris O, Keckes J, Tesch W, Bernstorff S, Purslow P, Fratzl P | title = Viscoelastic properties of collagen: synchrotron radiation investigations and structural model | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 357 | issue = 1418 | pages = 191–197 | date = February 2002 | pmid = 11911776 | pmc = 1692933 | doi = 10.1098/rstb.2001.1033 | veditors = Bailey AJ, Macmillan J, Shrewry PR, Tatham AS }}</ref>

===Uses===
[[file:Beretta Salami and Collagen Casing .jpg|right|150px|thumb|A salami and the collagen casing (below) it came in]]
Collagen has a wide variety of applications. In the medical industry, it is used in [[plastic surgery|cosmetic surgery]] and [[burn (injury)|burn surgery]]. An example of collagen use for food manufacturing is in [[casing (sausage)|casings for sausages]].

If collagen is subject to sufficient [[denaturation (biochemistry)|denaturation]], such as 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) of [[random coil]]s. This process describes the formation of [[gelatin]], which is used in many foods, including flavored [[gelatin dessert]]s. Besides food, gelatin has been used in pharmaceutical, cosmetic, and photography industries. It is also used as a [[dietary supplement]], and has been advertised as a potential remedy against the ageing process.<ref>{{cite journal | vauthors = Al-Atif H | title = Collagen Supplements for Aging and Wrinkles: A Paradigm Shift in the Fields of Dermatology and Cosmetics | journal = Dermatology Practical & Conceptual | volume = 12 | issue = 1 | pages = e2022018 | date = February 2022 | pmid = 35223163 | pmc = 8824545 | doi = 10.5826/dpc.1201a18 }}</ref><ref>{{cite journal | vauthors = Lawton G |title=The radical new theory that wrinkles actually cause ageing |journal=New Scientist |date=Apr 1, 2023 |url=https://www.newscientist.com/article/2366093-the-radical-new-theory-that-wrinkles-actually-cause-ageing/}}</ref><ref name="t159">{{cite journal | last1=Campos | first1=Luana Dias | last2=Santos Junior | first2=Valfredo de Almeida | last3=Pimentel | first3=Júlia Demuner | last4=Carregã | first4=Gabriel Lusi Fernandes | last5=Cazarin | first5=Cinthia Baú Betim | title=Collagen supplementation in skin and orthopedic diseases: A review of the literature | journal=Heliyon | volume=9 | issue=4 | date=2023 | issn=2405-8440 | pmid=37064452 | pmc=10102402 | doi=10.1016/j.heliyon.2023.e14961 | page=e14961| doi-access=free | bibcode=2023Heliy...914961C }}</ref>

From the Greek for glue, ''kolla'', the word collagen means "[[animal glue|glue]] producer" and refers to the early process of boiling the skin and [[tendon|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 [[bow (weapon)|bows]] about 1,500 years ago. The oldest glue in the world, [[radiocarbon dating|carbon-dated]] as more than 8,000 years old, was found to be collagen – used as a protective lining on rope baskets and [[embroidery|embroidered]] [[Textile|fabric]]s, to hold [[list of eating utensils|utensils]] together, and in crisscross decorations on [[human skull]]s.<ref>{{cite web |url=http://www.archaeology.org/online/news/glue.html |title=Oldest Glue Discovered |work=Archaeology |date=21 May 1998 | vauthors = Walker AA |url-status=live |archive-url=https://web.archive.org/web/20051217224604/http://www.archaeology.org/online/news/glue.html |archive-date=17 December 2005 }}</ref> Collagen normally converts to gelatin, but survived due to dry conditions. Animal glues are [[thermoplastic]], softening again upon reheating, so they are still used in making [[musical instrument]]s such as fine violins and guitars, which may have to be reopened for repairs – an application incompatible with tough, [[chemical synthesis|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 [[glyoxal|ethanedial]]) has been used to repair experimental incisions in rabbit [[lung]]s.<ref>{{cite journal | vauthors = Ennker IC, Ennker J, Schoon D, Schoon HA, Rimpler M, Hetzer R | title = Formaldehyde-free collagen glue in experimental lung gluing | journal = The Annals of Thoracic Surgery | volume = 57 | issue = 6 | pages = 1622–1627 | date = June 1994 | pmid = 8010812 | doi = 10.1016/0003-4975(94)90136-8 | doi-access = free }}</ref>

=== Cosmetics ===
{{more medical citations needed|section|date=March 2023}}
[[Bovine]] collagen is widely used in [[dermal filler]]s for [[Aesthetics|aesthetic]] correction of wrinkles and skin aging.<ref>{{Cite news | vauthors = Wasley A, Mendonça E, Zuker F |date=2023-03-06 |title=Global craze for collagen linked to Brazilian deforestation |language=en-GB |work=The Guardian |url=https://www.theguardian.com/environment/2023/mar/06/collagen-linked-brazilian-deforestation |access-date=2023-03-06 |issn=0261-3077}}</ref> Collagen cremes are also widely sold even though collagen cannot penetrate the skin because its fibers are too large.<ref name="harv">{{Cite web |date=2021-05-26 |title=Collagen |url=https://www.hsph.harvard.edu/nutritionsource/collagen/ |access-date=2023-03-06 |website=Harvard T.H. Chan School of Public Health: The Nutrition Source |language=en-us}}</ref> Collagen is a vital protein in [[skin]], [[hair]], [[Nail (anatomy)|nails]], and other tissues. Its production decreases with age and factors like sun damage and [[smoking]]. Collagen supplements, derived from sources like [[fish]] and [[cattle]], are marketed to improve skin, hair, and nails. Studies show some skin benefits, but these supplements often contain other beneficial ingredients, making it unclear if collagen alone is effective. There's minimal evidence supporting collagen's benefits for hair and nails. Overall, the effectiveness of oral collagen supplements is not well-proven, and focusing on a [[healthy lifestyle]] and proven skincare methods like [[Sunscreen|sun protection]] is recommended.<ref>{{cite web |title=Considering collagen drinks and supplements? |url=https://www.health.harvard.edu/blog/considering-collagen-drinks-and-supplements-202304122911 |website=Harvard Health Blog |publisher=Harvard Health Publishing |date=2023-04-12 |access-date=2024-07-19}}</ref>

==History==
The molecular and packing structures of collagen 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.<ref>{{cite journal | vauthors = Wyckoff RW, Corey RB, Biscoe J | title = X-Ray Reflections of Long Spacing from Tendon | journal = Science | volume = 82 | issue = 2121 | pages = 175–176 | date = August 1935 | pmid = 17810172 | doi = 10.1126/science.82.2121.175 | bibcode = 1935Sci....82..175W }}</ref><ref>{{Cite journal | vauthors = Clark G, Parker E, Schaad J, Warren WJ |title=New measurements of previously unknown large interplanar spacings in natural materials |journal=[[Journal of the American Chemical Society|J. Am. Chem. Soc.]] |year=1935 |volume=57 |issue=8 |page=1509 |doi=10.1021/ja01311a504 }}</ref> Research then concentrated on the conformation of the collagen [[monomer]], producing several competing models, although correctly dealing with the conformation of each individual peptide chain. The triple-helical "Madras" model, proposed by [[G. N. Ramachandran]] in 1955, provided an accurate model of [[quaternary structure]] in collagen.<ref name="Ram1955">{{cite journal | vauthors = Ramachandran GN, Kartha G | title = Structure of collagen | journal = Nature | volume = 176 | issue = 4482 | pages = 593–595 | date = September 1955 | pmid = 13265783 | doi = 10.1038/176593a0 | s2cid = 33745131 | bibcode = 1955Natur.176..593R }}</ref><ref name="Ram1954">{{cite journal | vauthors = Ramachandran GN, Kartha G | title = Structure of collagen | journal = Nature | volume = 174 | issue = 4423 | pages = 269–270 | date = August 1954 | pmid = 13185286 | doi = 10.1038/174269c0 | s2cid = 4284147 | bibcode = 1954Natur.174..269R }}</ref><ref>{{cite journal |journal=Resonance |volume=6 |issue=10 |url=http://www.ias.ac.in/resonance/php/toc.php?vol=06&issue=10 |title=GNR – A Tribute |author=Balasubramanian, D . |pages=2–4 |date=October 2001 |url-status=dead |archive-url=https://web.archive.org/web/20140110164101/http://www.ias.ac.in/resonance/php/toc.php?vol=06&issue=10 |archive-date=10 January 2014 |doi=10.1007/BF02836961 |s2cid=122261106 }}</ref><ref>{{cite journal | vauthors = Leonidas DD, Chavali GB, Jardine AM, Li S, Shapiro R, Acharya KR | title = Binding of phosphate and pyrophosphate ions at the active site of human angiogenin as revealed by X-ray crystallography | journal = Protein Science | volume = 10 | issue = 8 | pages = 1669–1676 | date = August 2001 | pmid = 11468363 | pmc = 2374093 | doi = 10.1110/ps.13601 }}</ref><ref>{{cite journal | vauthors = Subramanian E | title = G.N. Ramachandran | journal = Nature Structural Biology | volume = 8 | issue = 6 | pages = 489–491 | date = June 2001 | pmid = 11373614 | doi = 10.1038/88544 | s2cid = 7231304 | doi-access = free }}</ref> This model was supported by further studies of higher resolution in the late 20th century.<ref>{{cite journal | vauthors = Fraser RD, MacRae TP, Suzuki E | title = Chain conformation in the collagen molecule | journal = Journal of Molecular Biology | volume = 129 | issue = 3 | pages = 463–481 | date = April 1979 | pmid = 458854 | doi = 10.1016/0022-2836(79)90507-2 }}</ref><ref>{{cite journal | vauthors = Okuyama K, Okuyama K, Arnott S, Takayanagi M, Kakudo M | title = Crystal and molecular structure of a collagen-like polypeptide (Pro-Pro-Gly)10 | journal = Journal of Molecular Biology | volume = 152 | issue = 2 | pages = 427–443 | date = October 1981 | pmid = 7328660 | doi = 10.1016/0022-2836(81)90252-7 }}</ref><ref>{{cite journal | vauthors = Traub W, Yonath A, Segal DM | title = On the molecular structure of collagen | journal = Nature | volume = 221 | issue = 5184 | pages = 914–917 | date = March 1969 | pmid = 5765503 | doi = 10.1038/221914a0 | s2cid = 4145093 | bibcode = 1969Natur.221..914T }}</ref><ref>{{cite journal | vauthors = Bella J, Eaton M, Brodsky B, Berman HM | title = Crystal and molecular structure of a collagen-like peptide at 1.9 A resolution | journal = Science | volume = 266 | issue = 5182 | pages = 75–81 | date = October 1994 | pmid = 7695699 | doi = 10.1126/science.7695699 | bibcode = 1994Sci...266...75B }}</ref>

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.<ref name="Hulmes Miller 1979">{{cite journal | vauthors = Hulmes DJ, Miller A | title = Quasi-hexagonal molecular packing in collagen fibrils | journal = Nature | volume = 282 | issue = 5741 | pages = 878–880 | year = 1979 | pmid = 514368 | doi = 10.1038/282878a0 | s2cid = 4332269 | bibcode = 1979Natur.282..878H }}</ref><ref>{{cite journal | vauthors = Jésior JC, Miller A, Berthet-Colominas C | title = Crystalline three-dimensional packing is a general characteristic of type I collagen fibrils | journal = FEBS Letters | volume = 113 | issue = 2 | pages = 238–240 | date = May 1980 | pmid = 7389896 | doi = 10.1016/0014-5793(80)80600-4 | s2cid = 40958154 | doi-access = free | bibcode = 1980FEBSL.113..238J }}</ref><ref>{{Cite journal | vauthors = Fraser RD, MacRae TP |title=Unit cell and molecular connectivity in tendon collagen |journal=[[International Journal of Biological Macromolecules]] |year=1981 |volume=3 |issue=3 |pages=193–200 |doi=10.1016/0141-8130(81)90063-5 }}</ref> As with its monomeric structure, several conflicting models propose either that the packing arrangement of collagen molecules is 'sheet-like', or is [[microfibril]]lar.<ref>{{cite journal | vauthors = Fraser RD, MacRae TP, Miller A | title = Molecular packing in type I collagen fibrils | journal = Journal of Molecular Biology | volume = 193 | issue = 1 | pages = 115–125 | date = January 1987 | pmid = 3586015 | doi = 10.1016/0022-2836(87)90631-0 }}</ref><ref>{{cite journal | vauthors = Wess TJ, Hammersley AP, Wess L, Miller A | title = Molecular packing of type I collagen in tendon | journal = Journal of Molecular Biology | volume = 275 | issue = 2 | pages = 255–267 | date = January 1998 | pmid = 9466908 | doi = 10.1006/jmbi.1997.1449 }}</ref> 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.<ref>{{cite journal | vauthors = Raspanti M, Ottani V, Ruggeri A | title = Subfibrillar architecture and functional properties of collagen: a comparative study in rat tendons | journal = Journal of Anatomy | volume = 172 | pages = 157–164 | date = October 1990 | pmid = 2272900 | pmc = 1257211 }}</ref><ref>{{cite journal | vauthors = Holmes DF, Gilpin CJ, Baldock C, Ziese U, Koster AJ, Kadler KE | title = Corneal collagen fibril structure in three dimensions: Structural insights into fibril assembly, mechanical properties, and tissue organization | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 13 | pages = 7307–7312 | date = June 2001 | pmid = 11390960 | pmc = 34664 | doi = 10.1073/pnas.111150598 | doi-access = free | bibcode = 2001PNAS...98.7307H }}</ref><ref>{{cite journal | vauthors = Holmes DF, Kadler KE | title = The 10+4 microfibril structure of thin cartilage fibrils | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 46 | pages = 17249–17254 | date = November 2006 | pmid = 17088555 | pmc = 1859918 | doi = 10.1073/pnas.0608417103 | doi-access = free | bibcode = 2006PNAS..10317249H }}</ref> The microfibrillar structure of [[rat]] 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''.<ref name=Orgel>{{cite journal | vauthors = Orgel JP, Irving TC, Miller A, Wess TJ | title = Microfibrillar structure of type I collagen in situ | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 24 | pages = 9001–9005 | date = June 2006 | pmid = 16751282 | pmc = 1473175 | doi = 10.1073/pnas.0502718103 | doi-access = free | bibcode = 2006PNAS..103.9001O }}</ref><ref name=Okuyama>{{cite journal | vauthors = Okuyama K, Bächinger HP, Mizuno K, Boudko S, Engel J, Berisio R, Vitagliano L | title = Re: Microfibrillar structure of type I collagen in situ | journal = Acta Crystallographica. Section D, Biological Crystallography | volume = 65 | issue = Pt 9 | pages = 1009–10 | date = September 2009 | pmid = 19690380 | doi = 10.1107/S0907444909023051 | doi-access = free | bibcode = 2009AcCrD..65.1007O }}</ref><ref>{{cite journal|last1=Orgel|first1=Joseph|title=On the packing structure of collagen: response 0to Okuyama et al.'s comment on Microfibrillar structure of type I collagen in situ|journal=Acta Crystallographica Section D|volume=D65|issue=9|page=1009<!--|pages=1010-->|doi=10.1107/S0907444909028741|year=2009|bibcode=2009AcCrD..65.1009O |doi-access=free}}</ref>

== See also ==
{{col div|colwidth=30em}}
* [[Collagen hybridizing peptide]], a peptide that can bind to denatured collagen
* [[Hypermobility spectrum disorder]]
* [[Metalloprotease inhibitor]]
* [[Osteoid]], a collagen-containing component of bone
* [[Collagen loss]]
{{colend}}

== References ==
{{Reflist}}

{{Commons category}}
{{Connective tissue}}

{{Fibrous proteins}}

{{Authority control}}

[[Category:Collagens|*]]
[[Category:Structural proteins]]
[[Category:Edible thickening agents]]
[[Category:Aging-related proteins]]