Fibrillar Collagen Is Secreted and Assembled into Fibrils Outside the Cell

Fibrillar collagens are secreted proteins, produced primarily by fibroblasts in the ECM. Collagen biosynthesis and secretion follow the normal pathway for a secreted protein, described in detail in Chapters 13 and 14. The collagen α chains are synthesized as longer precursors, called pro-α chains, by ribosomes attached to the endoplasmic reticulum (ER). The pro-α chains undergo a series of covalent modifications and fold into triple-helical procollagen molecules before their release from cells (see Figure 20-27).

After the secretion of procollagen from the cell, extracellular peptidases remove the N-terminal and C-terminal propeptides. The resulting molecules, which consist almost entirely of a triple-stranded helix because of long stretches of the characteristic collagen repeating sequence motif Gly-X-Y, associate laterally to generate fibrils with a diameter of 50–200 nm. In fibrils, adjacent collagen molecules are displaced from one another by 67 nm, about one-quarter of their length. This staggered array produces a striated effect that can be seen in both light and electron microscopic images of collagen fibrils (see Figure 20-27, inset). The unique properties of the fibrillar collagens are mainly due to the formation of fibrils.

Short segments at either end of the fibrillar collagen α chains that are not composed of the repeating sequence motif Gly-X-Y, and thus are not triple-helical, are of particular importance in the formation of collagen fibrils. Lysine and hydroxylysine side chains in these segments are covalently modified by extracellular lysyl oxidases to form aldehydes in place of the amine group at the end of the side chain. These reactive aldehyde groups form covalent cross-links with lysine, hydroxylysine, and histidine residues in adjacent molecules. The cross-links stabilize the side-by-side packing of collagen molecules and generate a very strong fibril. The removal of the terminal propeptides and covalent cross-linking take place in the extracellular space to prevent the potentially catastrophic assembly of large fibrils within the cell.

The post-translational modifications of pro-α chains are crucial for the formation of mature collagen molecules and their assembly into fibrils. Defects in these modifications have serious consequences, which ancient mariners frequently experienced. For example, ascorbic acid (vitamin C) is an essential cofactor for the hydroxylases responsible for adding hydroxyl groups to proline and lysine residues in pro-α chains. In cells deprived of ascorbate, as in the disease scurvy, the pro-α chains are not hydroxylated sufficiently to form stable triple-helical procollagen at normal body temperature, and the procollagen that forms cannot assemble into normal fibrils. Without the structural support of collagen, blood vessels, tendons, and skin become fragile. Fresh fruit in the diet can supply sufficient vitamin C to support the formation of normal collagen. Historically, British sailors were provided with limes to prevent scurvy, leading to their being called “limeys.” Mutations in lysyl hydroxylase genes also can cause connective-tissue defects.

952