The term collagens encompasses a wide array of proteins each possessing a triple helix. They are hugely abundant in the animal kingdom being the most abundant proteins in mammals accounting for 30% of protein. To date there are a minimum of 29 genetically different members of the collagen family (Carter and Raggio 2009). These can be separated in to various subcategories including fibril forming collagens. Collagen type one is the most abundant member of this subfamily. These are exceptionally important biomechanically (Hulmes 2002) being present in almost every structurally important tissue and giving support to most organs. It does however have other roles such as controlling cell activity and extracellular matrix (ECM) formation and degradation by acting as a ligand toward specific cell receptors (Leitinger). Fibrilar collagens all have a similar primary structure which is essential for triple helix and fibril formation.
Collagen biosynthesis is far from a straightforward process as it involves numerous steps above the usual transcription translation process required for the formation of a protein. The collagen molecule is formed from 3 alpha subunits. In collagen type 1 there are 2 alpha 1 -chains and 1 alpha 2 chain. Each of these alpha chains is formed in to a left hand helix, with 3 amino acids (AAs) per turn, and these are brought together forming a right hand super helix. Each collagen molecule is comprised of a central triple helical region, which accounts for around 95% of the molecule. With a non helical region at either end. These non helical regions are known as telopeptides ( N-telopeptide at N-terminus and C-telopeptide at C-terminus). In order for the triple helical region to form correctly a strict pattern of AAs must be followed with every third AA being Glycine. this is due to the fact that in the centre of the triple helix there is insufficient space to accommodate side chains larger than the single hydrogen atom present on Glycine. The pattern may be written(Gly-X-Y)n where n is the number of repeats. N may be between 337 and 343. X and Y are often proline and hydroxy-proline. It follows that as the small side chain of Glycine is required in the centre of the triple helix the side chains of proline and hydroxyproline are orientated towards the outside of the molecule. Here they participate extensively in intermolecular and intramolecular interactions.
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The alpha polypeptide chains are synthesised as pre-procollagen on ribosomes of the rough endoplasmic reticulum (rER) of a cell (most commonly fibroblasts). Pre-procollagen has large N and C terminal globular domains and a 23 AA long (relatively short) hydrophobic signal peptide which allows it to penetrate the rough endoplasmic reticulum where it is removed by the signal peptidase enzyme. These are then joined at their respective C-terminuses and the triple helix formation advances towards the N-terminus resulting in a procollagen molecule. This process involves numerous specialised enzymes and chaperones which are required to ensure correct folding and carry out chain association and stabilization. (Kivirikko and Myllyla). The triple helix is stabilised by hydrogen bonds which form between the NH of glycine and the back bone of the c=o bond of the residue in the x position of the adjacent chain. this causes a lack of rotation around the calpha-atom of proline leading to stabilisation.
This process however cannot occur before the polypeptide chains undergo numerous post translational modifications (PTMs). These modifications include the hydroxylation of proline and lysine residues to form hydroxy-proline and hydroxy-lysine respectively; glycosylation (N or O linked), disulphide bonding, isomerisation, trimerisation and triple helix folding.
Procollagen molecules are then transported through the Golgi network being packed in to vesicles ready for secretion into extracellular space. There is then cleavage of the propeptides from both the N and C terminuses. This cleavage is enzymatic and utilises a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), tolloid-like proteinases and bone morphogenetic protein 1 (BMP1). This gives rise to the mature form of the molecule.
The mature collagen type 1 molecules then pack together in a spontaneous manner so that they are aligned in parallel. They are also staggered giving rise to a banded structure giving rise to a banded appearance in microscopy. The bands are repeated every 67nm, this distance is known as D. The 300nm length of a collagen molecule can be written as 4.4D with 0.4D representing the overlap distance of the ends. The fibril is then stabilised by widespread intermolecular cross linking.
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post translational modification
hydroxylation of lysine
Human type 1 collagen alpha1 chain contains 38 lysine residues: the helical region containing 36 and each of the telopeptides containing 1. An alpha 2 chain contains 31: helical region containing 30 and the n-telopeptide containing 1. It has been shown that the number of lysine molecules hydroxylated within a collagen molecule is more varied than in proline. Generally there is consistently around 50% hydroxylation of the proline residues regardless of the type of collagen, the tissue in which it is present or the physiological conditions. on the other hand the number of lysine residues hydroxylated varies significantly between collagens, between various tissues and even under different physiological conditions.(Uzawa, Yeowell et al.)
triple helix formation
Carter, E. M. and C. L. Raggio (2009). "Genetic and orthopedic aspects of collagen disorders." Current Opinion in Pediatrics 21(1): 46-54.
Hulmes, D. J. S. (2002). "Building collagen molecules, fibrils, and suprafibrillar structures." Journal of Structural Biology 137(1-2): 2-10.
Kivirikko, K. I. and R. Myllyla "Posttranslational enzymes in the biosynthesis of collagen: intracellular enzymes." Methods in Enzymology 82 Pt A: 245-304.
Leitinger, B. "Transmembrane collagen receptors." Annual Review of Cell & Developmental Biology 27: 265-290.
Uzawa, K., et al. "Lysine hydroxylation of collagen in a fibroblast cell culture system." Biochemical & Biophysical Research Communications 305(3): 484-487.