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Proteins: Collagen


Collagen is a major protein of the extracellular matrix and the most profuse protein in humans making up 30% of our skin, bone and connective tissues. Collagens are proteins that assemble into fibrous aggregates surrounding cells made up of three polypeptide chains with the characteristic repetitive amino acid sequence Gly-X-Y. Collagen itself confers thermal stability, mechanical strength and can interact with other molecules, depending of the way the collagen fibres aggregate. Collagens also have many other functions including cell adhesion and migration. We can observe collagens as long fibrils called fibrillar collagens and fibril-associated proteins. (Berg. et al, 2006) (Branden, et al, 1999)


Early fibre diffraction studies conducted by Pauling, Crick, Rich and others were able to show that each polypeptide chain of the collagen triple helix was folded into a left handed helix with 3.3 residues per turn and a 2.9 angstrom rise per residue. This stoichoiometry, although similar to the alpha helix, renders a much more extended helix, which explains why three helical molecules must aggregate to form a stable trimeric molecule.

  • rod shaped molecule 3000Å long and 15Å in diameter
  • made up of 3 helical polypeptide chains each containing 1000 residues
  • Chains are characterized by a repetitive Gly-X-Y amino acid motif where X and Y can be any amino acid.
  • The X and Y positions often correspond to proline and hydroxyl proline, respectively, resulting in an abundance of the glycine-proline-hydroxyproline sequence
  • The fact that glycine in present every third amino acid allows the 3 polypeptide chains to form right handed triple helices known as tropocollagen
  • Glycine residues face the core of the protein while proline and hydroxy-proline residues face outwards
  • The Gly-X-Y motif is a feature of all collagens, however the non-fibrilar collagens have disruptions of this motif
  • Tropocollagens assemble to form fibres and nextworks of collagen that we observe in tissue, bone and basement membrane
  • Hydrogen bonds between the hydroxylated residues stabilise the 3D structure of the tropocollagen
  • Covalent bonds form between tropocollagen molecules which stabilises the collagen fibril
  • Steric repulsion between proline and hydroxy-proline side chain tings stabilizes the helix


Amino acid sequence of collagen

A single polypeptide chain of collagen forms a left handed helix. Proline residue side chains face outwards from the helix while the smaller glycine side chains face inwards. This arrangement allows the collagen polypeptide chain to form a stable helix which the mechanical strength of collagen is built up from.

Three polypeptide chains combine to form and alpha helical strand of tropocollagen. Tropocollagen molecules further combine to form collagen fibrils. (Berg, et al, 2006)


collagen triple helix

Fibril associated collagens don’t cross link to form fibrils, instead the Gly-X-Y amino acid motif is regularly interrupted to give non-α helical motifs which reult in kinks in the collagen molecule. Additionally, some propeptides are not removed and so the globular regions will prevent association of the collagens into fibrils. Instead they mediate interactions between collagen fibrils and other extracellular molecules.



Common types of Collagen

As mentioned above, collagen is a major component in bone, tendon and connective tissues. there are 28 different types of collagen so far identified (see figure on nomenclature for how to name these) with type I being by far the most abundant. These are the most abundant types of collagen found in our body:

  • Type I– most widely occurring collagen found in skin, tendon, bone, cornea, lung, vasculature and is the component of scar tissue when a wound heals
  • Type II- major component of cartilage
  • Non fibrillar collagen type IV- also known as basement membrane collagen; is found at tissue boundaries
  • Type III- Makes up elastic tissues such as embryonic skin, lungs, blood vessels
  • Type V- less abundant, found in the cornea
  • Type XI- minor component in cartilage

(Mylyharju, et al, 2004)



    The fibrilar collagens are synthesised inside fibroblasts of loose connective tissue and in osteoblasts and chondroblasts of bone and cartillage. The fibrillar collagens are made in cells as precursors called procollagens; the procollagens still have N- and C- terminal propeptides that are not present in mature extracellular collagen. Procollagens will be modified repeatedly from when their first fold in the ER lumen to their deposition in the extracellular matrix. Overall collagen synthesis requires extensive post translational modifications.


    1. Transcription: Firstly, genes encoding the collagen molecule must be turned on and transcribed. There are 34 COL genes responsible.

    2. Translation into pre-pro-peptide: The mRNA transcript exits the nucleus and is translated by the ribosome into the signal sequence and pre-pro-peptide. Each pre-pro-peptide has N- and C- terminal propeptides and a signal sequence. The signal sequence on the N-terminal is recognized by a receptor on the endoplasmic reticulum which steers the pre-pro-peptide into the ER for post translational processing. The terminal propeptides also ensure that the triple stranded regions don’t get too close together in the cell and form fibrils prematurely in the Golgi and ER

    3. Pre-pro-peptide modification: The pre-pro-peptide is modified in three ways in the endoplasmic reticulum.

    • The proteinases cleave the N- signal sequence forming a propeptide.
    • Lysines and prolines in the propeptide are hydroxylated by lysyl hydroxylases and prolyl 4-hydroxylases, respectively. These hydroxyl groups facilitate intra-chain hydrogen bonding and stabilise the 3D structure. The 4-hydroxyproline molecules are also essential for formation of triple helical molecules
    • Glycosylation of some lysine hydroxyl groups to form galactosyllhydroxylysine and glucosylgalactosylhydroxylysine residues.
    • Some Asparagine residues in the C-propeptides are also glycosylated.
    • The three C-propeptides associate via specific recognition sequences, intramolecular and intermolecular disulphide bonds form.

    This causes the modified propeptide to twist to the left and eventually the three propeptides form a triple helix called procollagen. The procollagen is then packed into a vesicle and transported to the golgi body.


    3. Golgi modifications: The procollagen is modified by the addition of oligosaccharides and then packaged again into a secretory vesicle to be excreted into the extracellular matrix.


    4. Tropocollagen formation: Collagen peptidases in the extracellular matrix cleave the terminal N- and C- propeptides and spontaneous assembly of the collagen molecules into tropocollagen triple helices occurs.


    5. Collagen fibril: the enzyme lysyl oxidase is responsible for this step where hydroxyl groups on lysines and hydroxyl-lysines are converted into aldehyde groups which covalently bond between tropocollagen molecules to form a collagen fibril.


    6. Collagen fibre: some fibrils will then assemble into parallel bundles to form collagen fibres that confer great strength and flexibility; this occurs in some tissues such as tendons. We can think of the collagen fibre as a super cable of collagen fibrils.

    (Myllyharju, et al, 2004)


    Synthesis Summary

    Examples of Fibril assembly

    Bone Structure

    Fibrils in bone have a plywood alternate layer arrangement which doesn’t allow stretching

    (Tzaphildou, 2005)

    Connective tissues structure

    Fibrils in the extracellular matrix of connective tissue in skin are arranged like a woven basket which allows the connective tissue to resist stresses and strains in all directions.

    The image to the right shows dense irregular connective tissue, the black arrows indicate collagen fibrils overlapping in different directions which confer great flexibility and strength. See below for the diseases that result when collagen in connective tissue, particularly type I, is defective.

    (Holbrook, et al, 1982)

    Tendon structure

    In tendons the collagen fibrils will form fibres that assemble as parallel bundles which can be stretched without breaking

    Commercial Uses of Collagen

    Collagen is incredibly widely used in food, medicine, products and more. This is because collagen has many advantages as a biomaterial including:

    • It can be easily derived from other organisms and is very abundant
    • Collagen is biodegradable and non-toxic
    • As shown above, collagen can be combined in may different ways (sheets, sponges) to confer different properties
    • We can further modify collagen and introduce desirable properties
    • Collagen is essentially a biological plastic- with high tensile strength and little elasticity
    • Non-antigenic so it won't provoke an immune response

    Collagen as a supplement

    Collagen is marketed as a popular supplement for healthier joints, hair and skin. Although, the effectiveness of oral administration of collagen is questionable as it is probable that the collagen is broken down by digestive enzymes before any effective absorption takes place.

    Collagen injections

    Collagen injections are popular as an anti wrinkle agent; as we age our collagen looses its uniform structure and begins to unravel, this leads to loss of elasticity of the skin and wrinkles forming. By injecting collagen some practitioners claim they can temporarily restore this elasticity and give the appearance of smoother skin.

    Diet agents

    Diet products use hydrolysed collagen which results in a bulky collagen mass which manufacturers claim leads to feeling full quicker.

    Medical uses

    Cosmetic Surgery

    Collagen is increasingly used in cosmetic surgery for the aesthetic improvement of burns and bone remodelling.

    Bone filling/ reconstructing

    Demineralized bone collagen is combined with polymers such as PGMA and antibiotic to form a composite. The strength of collagen allows it to act as a scaffolding material for new bone material to grow around.

    Collagen is used in burns and wound dressings

    Massive burns and severe wounds pose a clinical problem as they need to be covered to avoid infection, collagen has been added to grafts to cover burns and has been shown to improve healing and reduce infection. It has also been shown that collagen has hemostatic blood clotting properties.

    Collagen has even inspired art!

    The artist Julian Vos-Andreae has created sculptures based on the alpha-helical structure of collagen unravelling which is significant for as we age our collagen molecules become weaker which leads to the formation of wrinkles.

    Collagen deficiency diseases

    Inherited conditions arise where the gene defect affects either the collagen molecule itself or post translational modifications such as propeptide cleavage and hydroxylation. It only takes the knockout of collagen encoding genes to see how essential they are for the proper functioning of the body.

    Osteogenesis imperfecta, more commonly known as brittle bones disease, is a congenital disease caused by a defect in the gene encoding collagen type I; remember collagen type I is the most abundant collagen and is responsible for the strength and integrity of bone and ligaments. Multiple mutations can affect this gene and the severity of disease depends on the specific mutations. Mutations in the collagen encoding genes will mean collagen synthesised is imperfect and will not aggregate to form suitable triple helices and collagen fibrils. As a result the bones are weakened, sufferers can easily break their bones and can present with blue sclera. As collagen type I is also a component in ligaments, sufferers often have hyper motility.

    Other collagen deficiency diseases include chondrodysplasias (defective cartilage) and Bethlem myopathy.

    Another example is Ehlors Danlos syndrome which is caused by defective lysyl oxidase which leads to insufficient production of cross links between fibres to stabilise collagen fibrils. This leads to fragile, stretchable skin and blood vessels and hyper motility.


    Useful links and further reading

    Here is a video which summarizes the importance and structural applications of collagen quite well:

    Another video depicting the structure of collagen and its arrangement in connective tissue:

    Here is a website for a collagen research lab in new jersey; some of their research into collagen and disease is very interesting:

    Biochemistry by Berg, et al has a nice section on the structure of collagen and amino acid sequence page 45-46


    • Berg, J. M., Tymoczo, J. L. & Stryer, L., 2006. Biochemistry. 6 ed. USA: W.H Freeman and Company.
    • Kadler, K.E., Baldock, C., Bella, J. & Boot-Handford, R.P. (2007) Collagens at a glance. J. Cell Sci. 120(Pt 12):1955-8.
    • Mylyharju, J. & Kivirkko, k. I., 2004. Collagens, modifying enzymes and their mutations in humans, flies and worms. 20(1), pp. 33-43.
    • Tzaphlidou, M., 2005. The role of collagen in bone structure: an image processing approach. Micron, Volume 36, pp. 593-601.
    • Wolfgang, F., 1998. Collagen- Biomaterial for drug delivery. European Journal of Pharmaceuticals and Biopharmaceutics, Volume 45, pp. 113-136.
    • Holbrook, K. & Byers, P., 1982. Structural abnormalities in the dermal collagen and elastic elastic matrix from skin of patients with inherited connective tissue disorders. The Journal of Investigative Dermatology, Volume 79, pp. 7s-16s.
    • Trentham, D. et al., 1993. Effects of Oral Administration of type II collagen on rheumatoid arthritis. Science, Volume 261, pp. 1727-1730.
    • Branden, C. & Tooze, J., 1999. Introduction to protein structure. New York: Garland Publishing, inc.
    • Panduranga, K., 1995. Recent developments of collagen-based materials for medical applications and drug delivery systems. Journal of Biomaterials Science, 7(7), pp. 623-645.





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