The Structure and Function of Collagen
Collagen Fibrils and Fibers
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 . 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 . 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 .
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  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 .
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 . 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 .
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
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 . 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 . 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.
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 . 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 . 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 .
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 . 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 .
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. .
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 .
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