How are the fibril forming interstitial collagens synthesized

How are the fibril forming interstitial collagens synthesized?

1. There are at least 30 distinct genes that encode the various collagen chains. In adults, collagen gene expression is subject to positive regulation (transforming growth factor [TGF]-β) and negative regulation (interferon-γ and tumor necrosis factor [TNF]-α). The collagen genes studied thus far contain coding sequences (exons) interrupted by large, noncoding sequences (introns). The DNA is transcribed to form a precursor mRNA, which is processed to functional mRNA by excising and splicing, which removes mRNA coded by introns. The processed mRNAs leave the nucleus and are transported to the polyribosomal apparatus in the rough endoplasmic reticulum for translation into polypeptide α-chains.

2. The polypeptide α-chains (known as preprocollagen) are hydroxylated by prolyl hydroxylase and lysine hydroxylase to aid in the crosslinking of the α-chains. These enzymes require O , Fe 2+ , α-ketoglutarate, and ascorbic acid (vitamin C) as cofactors. Hydroxyproline is critical to the stable formation of the triple helix. Decrease in the hydroxyproline content as seen in scurvy (ascorbic acid deficiency) results in unstable molecules that lose their structures and are broken down by proteases.

3. Glycosylation of hydroxylysine residues by adding glucose or galactose monomers. Three of these hydroxylated and glycosylated polypeptide α-chains (preprocollagen) twist into a triple helix forming procollagen. Procollagen is packaged in vesicles that go to the Golgi apparatus. In the Golgi, oligosaccharides are added to the procollagen which is then secreted into the extracellular space.

4. Outside the cell, procollagen peptidases on the cell membrane remove the amino and carboxyl terminal telopeptides converting procollagen into tropocollagen. This step is absent in the vascular type of Ehlers–Danlos syndrome that fails to synthesize type III collagen.

5. There is an assembly of these tropocollagen molecules by a quarter-stagger shift. In cartilage, cartilage oligomeric matrix protein (COMP) is important in this quarter-stagger arrangement. Lysyl oxidase, an extracellular, copper-dependent enzyme, acts on lysines and hydroxylysines producing aldehyde groups that form covalent bonds between the tropocollagen molecules. This polymer of tropocollagen molecules is called a collagen fibril. Mutations of COMP can cause achondroplasia and multiple epiphyseal dysplasia.

6. End-to-end and lateral aggregation of collagen fibrils to form a collagen fiber.

Each collagen molecule measures 300 nm in length and 1.5 nm in width and has five charged regions 68 nm apart. The charged regions align in a straight line when the fibrils are formed, even though the individual molecules themselves are staggered a quarter of their lengths in relation to each other. One can easily see that there are multiple steps where defects in collagen biosynthesis could result in abnormalities leading to disease ( Fig. 3.2 ; see also Chapter 55 : Heritable Connective Tissue Disease).

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