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Collagen is synthesized intracellularly in the fibroblasts (or in osteoblasts of bone and chondroblasts of cartilages) as a large precursor, called preprocollagen. Like most secreted proteins,collagen is synthesized on ribosomes. It is then secreted in to the extra cellular matrix. After enzymatic modification,the mature collagen monomers aggregate and become cross linked to form collagen fibrils. The synthesis of collagen (Figure-3) involves three stages-

A) Intracellular steps

B) Secretion

C) Extra-cellular steps

A) Intracellular steps- The processes involved inside the cell in the synthesis of collagen are as folllows-

a) Formation of Pro- α chains– The newly synthesized polypeptide precursors of α chains contain, a leader sequence(a special amino acid sequence at the amino terminal end).This sequence acts as a signal that the polypeptide being synthesized is destined to leave the cell. The signal sequence directs the passage of the polypeptide chain in to the cisternae of the rough endoplasmic reticulum. Signal peptidase cleaves the signal sequence in the endoplasmic reticulum to yield a precursor of collagen called pro-α chain.

b) Hydroxylation- The pro -α chains are processed by a number of enzymatic steps within the lumen of the RER. The proline and lysine residues are hydroxylated by  prolyl and lysyl hydroxylases to form hydroxy proline and hydroxy lysine respectively (Figure-1). The reactions can be represented as follows-

 Hydroxylation of proline and lysine in collagen synthesis

Figure-1- Prolyl and lysyl hydroxylases require molecular oxygen,  ascorbic acid(vitamin C) and α-keto (oxo) glutarate for their action.

Impaired prolyl and lysyl hydroxylation , as in ascorbic acid (vitamin C) deficiency, leads to improper cross linking of collagen fibers , thus a weak collagen results with decreased tensile strength of the assembled fibers. The resulting disease, scurvy is manifested by  bleeding gums, bruises, weak bones, all due to weak collagen.

c) Glycosylation- Some of the hydroxy lysines are modified by glycosylation with galactose or galactosyl-glucose through an O-glycosidic linkage, a glycosylation site that is unique to collagen (Figure-2).

 glycosylation of collagen

Figure-2- The galactose and glucose residues are added sequentially by galactosyl and glucosyl transferases. The extent of glycosylation is different in different tissues

d) Assembly – After hydroxylation and glycosylation the  pro-α chains form procollagen, a precursor of collagen. The procollagen molecule contains polypeptide extensions (extension peptides) at both its amino and carboxyl terminal ends, neither of which is present in mature collagen. Both extension peptides contain cysteine residues. While the amino terminal propeptides forms only intrachain disulfide bonds, the carboxyl terminal propeptides form both intrachain and interchain disulfide bonds. Formation of these disulfide bonds, assists in the assembly of the three collagen molecules to form the triple helix, winding from the carboxyl terminal end. After formation of the triple helix, no further hydroxylation of proline or lysine or glycosylation of hydroxylysines can take place. Self-assembly is a cardinal principle in the biosynthesis of collagen (Figure-3)

B) Secretion- The procollagen  molecules are translocated to the Golgi apparatus where they are packaged in secretory vesicles. The vesicles fuse with the cell membrane, causing the release of procollagen molecules in to the extracellular space (Figure-3)

C) Extracellular steps– The processes involved outside the cell to form mature collagen molecules are as follows (Figure-3)-

a) Cleavage of amino and carboxyl terminal propeptides- Following secretion from the cell by way of the Golgi apparatus, extracellular enzymes called procollagen aminoproteinase and procollagen carboxyproteinase remove the extension peptides at the amino and carboxyl terminal ends, respectively, releasing triple helical collagen molecules. Cleavage of these propeptides may occur within crypts or folds in the cell membrane.

b) Formation of collagen fibrils– Once the propeptides are removed, the triple helical collagen molecules, containing approximately 1000 amino acids per chain, spontaneously assemble into collagen fibers. Collagen types that form long rod-like fibers in tissues are assembled by lateral association of these triple helical units into a “quarter staggered” alignment such that each is displaced longitudinally from its neighbor by slightly less than one-quarter of its length . This arrangement is responsible for the banded appearance of these fibers in connective tissues.

c) Cross link formation– Collagen fibers are further stabilized by the formation of covalent cross-links, both within and between the triple helical units. These cross-links form through the action of lysyl oxidase, a copper-dependent enzyme that oxidatively deaminates the Ʃ-amino groups of certain lysine and hydroxylysine residues, yielding reactive aldehydes. Such aldehydes can form aldol condensation products with other lysine- or hydroxylysine-derived aldehydes or form Schiff bases with the Ʃ-amino groups of unoxidized lysines or hydroxylysines. These reactions, after further chemical rearrangements, result in the stable covalent cross-links that are important for the tensile strength of the fibers. Histidine may also be involved in certain cross-links (Figure-4).

Steps of collagen synthesis


Figure-3- Showing the steps of collagen synthesis and formation of mature collagen

The cross links are essential for the achieving the tensile  strength necessary for the proper functioning of the connective tissue. Therefore any mutation that interferes with the ability of collagen to form cross linked fibrils affects the stability of the collagen.

 Overview of structure of collagen

Figure-4- Overview of collagen structure

Several collagen types do not form fibrils in tissues.

The types and organization of collagens are dictated by the structural role played by specific collagen in specific tissues. In some tissues collagen may be found in a gel like structure to give support as in extracellular matrix or the vitreous humor of eye. In other tissues, collagen may be bundled in tight, parallel fibers that provide greater strength, as in tendons. In cornea of eye, collage is stacked so as to transmit the light with a minimum of scattering. Collagen of bone occurs as fibers arranged at an angle to each other so as to resist mechanical from any direction.

The collagen can be organized in to three groups based on the location and functions in the body-

1. Fiber forming

Type I, II and III are the fibrillar collagens, and have the rope like structure. In the electron microscope, these linear polymers of fibrils have characteristic banding patterns, reflecting the regular staggered packing of the individual collagen molecules in the fibril. Type I fibers are found in supporting elements of high tensile strength (Table -1), whereas the fibers formed from type II collagen are restricted cartilaginous structures. The fibers derived from Type III collagen are found in more distensible tissues such as blood vessels.

2. Net work forming collagens

Type IV and VII form a three dimensional mesh work, instead  of making fibrils. This meshwork forms a major part of basement membranes (Table-1).

3. Fibril associated collagens

Type IX and XII bind to the surface of collagen fibrils, linking these fibrils to one another and to other components in the extra cellular matrix (Table-1).

 Table-1- Types and Tissue distribution of collagens

Type Tissue distribution
1.Fibril forming  
Type I Skin, bone, tendon, blood vessels and cornea
Type II Cartilage, intervertebral disc, vitreous body
Type III Blood vessels, fetal skin
2. Net work forming  
Type IV Basement membrane
Type VII Beneath stratified squamous epithelium
3.Fibril Associated  
Type IX Cartilages
Type X Tendons, ligaments and some other tissues


Once formed, collagen is relatively metabolically stable. However, its breakdown is increased during starvation and various inflammatory states. Excessive production of collagen occurs in a number of conditions, eg, hepatic cirrhosis.

Composition of different type of collagen

Collagen,  is not one protein but a family of structurally related proteins. The different collagen proteins have very diverse functions. The different types of collagen are characterized by different polypeptide compositions. Each collagen is composed of three polypeptide chains, which may be all identical or may be of two different chains (Table-2)

Type I collagen, the most abundant, is composed of two identical α1(I) chains and a third α2(I) chain that is the product of a different gene and differs slightly in its amino acid sequence. Type II collagen, the fibrillar collagen of cartilage, is composed of three identical α(II) chains. Type III collagen is composed of three identical α1(III) chains. It is found in small amounts in many tissues that contain type I collagen and in large amounts in major blood vessels. Type IV collagen is composed of three α chains synthesized from any of six different genes. It is found in basement membranes where it self-assembles with laminins and other macromolecules into a complex three-dimensional network to provide a diffusion barrier in the renal glomerulus, pulmonary alveolus, and other tissues.

Table-2- Composition of collagen types

Type of Collagen Composition
Type I [alpha1(I)]2alpha2(I).
Type II [alpha1(II)]3.
Type III [alpha1(III)]3
Type IV [alpha (IV)]3


Degradation of collagen and diseases- to be continued in the next post.

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