ArtsAutosBooksBusinessEducationEntertainmentFamilyFashionFoodGamesGenderHealthHolidaysHomeHubPagesPersonal FinancePetsPoliticsReligionSportsTechnologyTravel

The Structure and Function of Collagen

Updated on February 8, 2015

Collagen Fibrils and Fibers

Collagen Fibrils and Fibers
Collagen Fibrils and Fibers | Source

A General Introduction to Collagen

The most abundant connective tissue in the extracellular matrix is fibrous collagen. They are centrally involved in formation of fibrillar and microfibrillar networks in the extracellular matrix (ECM) and basement membranes [13]. There are many classes of collagenous structures in the ECM, including fibrils, networks, and trans membrane collagenous domains. In humans collagen makes up one-third of the total proteins synthesized. It accounts for three-quarters of the dry weight of the skin. The interstitial type I, II and III collagens form a triple helix composed of three α-chains. A strictly repeated Gly-X-Y sequence allows for the formation of a triple helical conformation. Thus far, 28 different types of collagen with 46 different polypeptide chains have been discovered [12]. Originally it was thought the function of collagen was limited; the discovery of additional protein domains has led to a wide variety of known functions of collagen. For example, type IV collagens are more flexible and form meshworks in basement membranes versus type VI collagens which contain more disulfide bonds which allows them to form long and stable microfibrils.

The exploration of collagen expression and function leads to a better understanding of diseases such as osteogenesis imperfect, epidermolysis bullosa, Alport syndrome, and Ehler’s Danlos Syndrome. The network forming ability of collagen could contribute to scaffold formation and tissue repair and regeneration which has applications in the medical and cosmetic industry [13].

Gap and Overlap Regions of Collagen and fiber assembly
Gap and Overlap Regions of Collagen and fiber assembly | Source

Structure of Collagen

The primary residue triplets that comprise the collagen molecule are Gly-X-Y. The X and Y positions differ in their steric property which leads to variations in the residues. For example, bulky side-chains are found preferentially in the X position [10] and large non-polar residues are clustered in the X positions as well [10, 11]. The triple-helix conformation tends to bond at similar axial levels and orientations with X and Y positions from neighboring chains. This property allows for salt bridge formation in type I collagen which are evenly distributed along the molecule. These results suggest that the distribution of large non-polar residues and imino pairs are related to the interactions between the molecules in the collagen fibril and that the hydrophobic interaction potential serves to determine the three-dimensional packing of the molecules within a fibril [11].

The crystalline arrays of type I collagen molecules are composed of gap and overlap regions. In the overlap region the interactions between cyclic sets are strong leading to a quasi-hexagonally packed array [11]. Information on the gap regions of the fibrils is more difficult to obtain due to the lack of any significant contribution on Bragg reflections. Absence of activity on Bragg reflections suggested that these segments are more mobile than those in the overlap region. This might contribute to collagen’s tensile strength yet flexibility properties. Four properties were found to contribute to the increased mobility of the gap region versus the overlap region: 1) Reduced packing density. 2) Lower content of triplets containing to imino acid residues which are known to stabilize the collagen helix. 3) Lower content of hydroxyproline residues known to increase the denaturation temperature. 4) Lower concentration of aromatic residues known to confer rigidity in globular proteins [9].

Synthesizing Collagen In Vivo

Collagen synthesis is a multistep process involving many organelles of the cell. Regulation of collagen synthesis is based on cell type but other factors such as cytokines, TGF-β, fibroblast-growth-factors, and insulin-like-growth-factors also control synthesis. Alternative splicing has been reported for various types of collagen possibly leading to the various polypeptide chains discovered. Many collagen genes revealed complex intro-exon patterns ranging from 3-117 exons. mRNA is translated on ribosomes in the rough endoplasmic reticulum and synthesized into preprocollagen molecules. Procollagen molecules undergo multiple steps of post-translational modification including hydroxylation of proline and lysine residues, C-propeptide disulfide bond formation, alignment of C-terminal domains, and finally initiation of the triple helix progressing toward the N-terminus. Further enzymes such as peptidyl-prolyl cis-trans-isomerase (PPI) and chaperones such as HSP47 aid in the proper folding of procollagen chains.

The triple-helical molecules are then packaged into the Golgi compartments into secretory vesicles and released into the ECM. ECM formation of fibrils has largely been studied in vitro. Fibril-forming collagens such as type I, II, III, V and XI spontaneously aggregate into ordered fibrillar structures in vitro. The ability for self-assembly is encoded in the structure of collagen. Hydrophobic and electrostatic interactions are thought to cause aggregation into five stranded fibrils which causes further aggregation into larger fibrils. The fibrils can then be oriented into distinct types of tissues in parallel configurations or a meshwork of fibers and are stabilized by covalent cross-links which contribute to the resilience of the fibrils [12, 13]. An outline of collagen synthesis and assembly model is represented below.

Collagen Synthesis and Assembly Model

How the collagen protein is assembled from mRNA to a fiber.
How the collagen protein is assembled from mRNA to a fiber.

Artificial Synthesis - Its Limitations

The structural basis for cell-mediated regulation of fibril assembly was studied using quantitative mass mapping and electron microscopy. As opposed to collagen fibrils growing in vitro, the tips of fibrils formed in chick tendons exhibit an abrupt plateau in the axial mass distribution. When individual tendon fibrils were analyzed it was observed that a growth in length could occur independently of diameter and involves regulated tip growth. This could be a possible explanation of how cells can synthesize long fibrils of collagen that are very constant in diameter when the ECM is assembled [7]. However, achieving a constant diameter in artificial collagen synthesis has been a challenge.

In vitro synthesis of collagen has shown promising results. Artificial collagen fibrils that display some properties of natural collagen fibrils are now available using chemical synthesis and self-assembly [12]. It is known that the removal of the N and C-propeptides by procollagen N and C proteinases generates collagen molecules that can self-assemble into fibrils. An in vitro system has been developed where purified procollagen is cleaved with procollagen N-proteinase and the resultant pCcollagen is incubated with purified procollagen C-proteinase. A peculiar feature of this system is growth exclusively from the N-termini oriented toward the tip of the fibril. Another limitation of the in vitro system is that fibrils synthesized in this manner do not show even axial mass distribution and as such do not have uniform diameter shafts as in vivo collagen fibrils do [7, 8].

Initiating a self-assembly model that is as accurate as possible could serve a potential role in tissue regeneration therapies.

Gap and overlap model of collagen
Gap and overlap model of collagen

Degradation of Collagen and Loss of Function

It is known that collagen degradation is promoted by oxidative stress [3, 4]. One study done looked at the degeneration of gingival collagen density in 344 male rats aged 4-8 months. Tomarina, a dental paste consisting of anti-inflammatory (pygnogenol, dipotassium glycyrrhizate, tocopherol acetate, allantoin, ligusticum extract and peony extract), anti-bacterial (cetylpyridinium chloride) was applied to the gingival sulcus and rats were examined for 10 months. The experimental group showed a smaller increase in serum oxidative stress with ageing and there was no decrease in gingival collagen observed, as opposed to the control group with saw decreased levels [2]. The results of the study were consistent with polyphenol research, which suggests that polyphenols act as antioxidants and the effect reduces the risk of degenerative diseases [1]. Further experimentation needs to be performed in order to determine the impact of these topical applications in older populations of rats since it is known that decreased collagen synthesis and loss of responsiveness to growth factors occurs in aged cells in vivo or in vitro [4].

Another study showed that relative basal levels of collagen synthesis by dermal fibroblasts from 3 newborn donors (1 day old) were greater than those from the exposed and unexposed skin of 4 elderly donors [4]. When fibroblasts from 1 day old newborns and 60-76 year old individuals were cultured in monolayer and collagen gel it was shown that photoaged fibroblasts in collagen gel showed greater basal collagen synthesis than aged fibroblasts in the same individuals but similar basal collagen synthesis in monolayer culture. In the monolayer, culture the responsiveness to ascorbic acid in newborn fibroblasts was greater than in photoaged and aged fibroblasts. The responsiveness of photoaged and aged fibroblasts to transforming growth factor-beta and interferon-gamma seems to be the same as in newborn fibroblasts even though basal levels of collagens synthesis are downregulated via photoaging or aged cells [4].

Several in vivo and in vitro studies show that there is an inverse relationship with the age of donors and the levels of collagen synthesis [5, 6].

Other Functions of Collagen

Specific receptors mediate the interaction with collagens, like integrins, discoidin-domain receptors, glycoproteins VI. Signaling defines adhesion, differentiation, growth, and survival of the cell. Their biological processes may not be limited to these activities. They play a role in the cellular microenvironment functioning in the delivery of growth factors and cytokines and function in the role or organ development. [13].

These important properties have generated pharmaceutical interest as well as the discovery of non-collagenous fragments of collagens IV, XV, and XVIII, called matricryptins, which have been shown to influence angiogenesis and tumorgenesis [14].

3D Structure of Collagen
3D Structure of Collagen | Source


  1. Chiva-Blanch G., Visoli F., Polyphenols and health. Moving beyond antioxidants. J Berry Res. 2012; 2(2): 63-71
  2. Irie K., Tomofuji T., Ekuni D., et al. Anti-ageing effects of dentrifices containing anti-oxidative, anti-inflammatory, and anti-bacterial agents (Tomarina) on gingival collagen degradation in rats. Journal of Oral Biology. 2013; 59: 60-65
  3. Alge-Priglinger C. S., Kreutzer T., Obholzer K., et at. Oxidative stress-mediated induction on MMP-1 and MMP-3 in human RPE cells. Investigative Ophthalmology and Visual Science Journal. 2009; 50(11): 495-503.
  4. Chung H. J., Youn H. S., Kwon S. O., et al. Regulations of collagen synthesis by ascorbic acid, transforming growth factor-beta and interferon-gamma in human dermal fibroblasts cultured in three-dimensional collagen gel are photoaging and aging-independent. Journal of Dermatological Science. 1997; 15: 188-200
  5. Johnson B. D., Page R. C., Narayanan A. S., et al. Effects of donor age on protein and collagen synthesis in vitro by human diploid fibroblasts. Laboratory investigation. 1986; 55: 490-496
  6. Philips C. L., Combs S. B., Pinnell S. R. Effects of ascorbic acid on proliferation and collagen synthesis in relation to the donor age of human dermal fibroblasts. Journal of Investigative Dermatology 1994; 103: 228-232
  7. Holmes D. F., Graham H. K., Kadler E. K. Collagen fibrils forming in developing tendons show an early and abrupt limitation in diameter at the growing tips. Journal of Molecular Biology. 1998; 283: 1049-1058
  8. Kadler K. E., Hojima Y., Prockop D. J. Assembly of collagen fibrils de novo by enzymic cleavage of the type I pCcollagen by procollagen C-proteinase. Assay of critical concentration demonstrates that the process is an example of classical entropy-driven self-assembly. Journal of Biological Chemistry. 1987; 268: 15696-15701
  9. Fraser R. D. B., MacRae T. P. Molecular packing in type I collagen fibrils. Journal of Molecular Biology. 1987; 193: 115-125
  10. Traub W. Some Stereochemical Implications of the Molecular Conformation of Collagen. Israel Journal of Chemistry. 1974; 12: 435-439
  11. Jones Y. E., Miller A. Analysis of structural design features in collagen. Journal of Molecular Biology. 1991; 218: 209-219
  12. Shoulders M. D., Rainer T. R. Collagen structure and stability. Annual Reviews of Biochemistry. 2009; 78: 929-958
  13. Gelse K., Poschl E., Aigner., Collagens – structure, function, and biosynthesis. Advanced Drug Delivery Reviews. 2003; 55: 1531-1546
  14. Ortega N., Werb Z. New functional roles for non-collagenous domains of basement membrane collagens. Journal of Cell Science. 2002; 115: 4201-4214

© 2015 Laura Writes


    0 of 8192 characters used
    Post Comment

    No comments yet.


    This website uses cookies

    As a user in the EEA, your approval is needed on a few things. To provide a better website experience, uses cookies (and other similar technologies) and may collect, process, and share personal data. Please choose which areas of our service you consent to our doing so.

    For more information on managing or withdrawing consents and how we handle data, visit our Privacy Policy at:

    Show Details
    HubPages Device IDThis is used to identify particular browsers or devices when the access the service, and is used for security reasons.
    LoginThis is necessary to sign in to the HubPages Service.
    Google RecaptchaThis is used to prevent bots and spam. (Privacy Policy)
    AkismetThis is used to detect comment spam. (Privacy Policy)
    HubPages Google AnalyticsThis is used to provide data on traffic to our website, all personally identifyable data is anonymized. (Privacy Policy)
    HubPages Traffic PixelThis is used to collect data on traffic to articles and other pages on our site. Unless you are signed in to a HubPages account, all personally identifiable information is anonymized.
    Amazon Web ServicesThis is a cloud services platform that we used to host our service. (Privacy Policy)
    CloudflareThis is a cloud CDN service that we use to efficiently deliver files required for our service to operate such as javascript, cascading style sheets, images, and videos. (Privacy Policy)
    Google Hosted LibrariesJavascript software libraries such as jQuery are loaded at endpoints on the or domains, for performance and efficiency reasons. (Privacy Policy)
    Google Custom SearchThis is feature allows you to search the site. (Privacy Policy)
    Google MapsSome articles have Google Maps embedded in them. (Privacy Policy)
    Google ChartsThis is used to display charts and graphs on articles and the author center. (Privacy Policy)
    Google AdSense Host APIThis service allows you to sign up for or associate a Google AdSense account with HubPages, so that you can earn money from ads on your articles. No data is shared unless you engage with this feature. (Privacy Policy)
    Google YouTubeSome articles have YouTube videos embedded in them. (Privacy Policy)
    VimeoSome articles have Vimeo videos embedded in them. (Privacy Policy)
    PaypalThis is used for a registered author who enrolls in the HubPages Earnings program and requests to be paid via PayPal. No data is shared with Paypal unless you engage with this feature. (Privacy Policy)
    Facebook LoginYou can use this to streamline signing up for, or signing in to your Hubpages account. No data is shared with Facebook unless you engage with this feature. (Privacy Policy)
    MavenThis supports the Maven widget and search functionality. (Privacy Policy)
    Google AdSenseThis is an ad network. (Privacy Policy)
    Google DoubleClickGoogle provides ad serving technology and runs an ad network. (Privacy Policy)
    Index ExchangeThis is an ad network. (Privacy Policy)
    SovrnThis is an ad network. (Privacy Policy)
    Facebook AdsThis is an ad network. (Privacy Policy)
    Amazon Unified Ad MarketplaceThis is an ad network. (Privacy Policy)
    AppNexusThis is an ad network. (Privacy Policy)
    OpenxThis is an ad network. (Privacy Policy)
    Rubicon ProjectThis is an ad network. (Privacy Policy)
    TripleLiftThis is an ad network. (Privacy Policy)
    Say MediaWe partner with Say Media to deliver ad campaigns on our sites. (Privacy Policy)
    Remarketing PixelsWe may use remarketing pixels from advertising networks such as Google AdWords, Bing Ads, and Facebook in order to advertise the HubPages Service to people that have visited our sites.
    Conversion Tracking PixelsWe may use conversion tracking pixels from advertising networks such as Google AdWords, Bing Ads, and Facebook in order to identify when an advertisement has successfully resulted in the desired action, such as signing up for the HubPages Service or publishing an article on the HubPages Service.
    Author Google AnalyticsThis is used to provide traffic data and reports to the authors of articles on the HubPages Service. (Privacy Policy)
    ComscoreComScore is a media measurement and analytics company providing marketing data and analytics to enterprises, media and advertising agencies, and publishers. Non-consent will result in ComScore only processing obfuscated personal data. (Privacy Policy)
    Amazon Tracking PixelSome articles display amazon products as part of the Amazon Affiliate program, this pixel provides traffic statistics for those products (Privacy Policy)