Figure 1. Biosynthesis of fibrillar collagens.

The biosynthesis of type I collagen and other fibrillar collagens can be divided into intracellular (parts a–c) and extracellular (parts d–f) steps. The first intracellular step involves the synthesis of procollagen polypeptides from any of 42 distinct collagen gene transcripts (part a). Procollagens are post-translationally modified within the cisternae of the endoplasmic reticulum (ER) by prolyl 4-hydroxylase α-subunit isoform 1 (P4HA1), P4HA2 and P4HA3 and by procollagen-lysine 2-oxyglutarate 5-dioxygenase 1 (PLOD1), PLOD2 and PLOD3 lysyl hydroxylase enzymes (part b). Hydrolysine residues can be further modified to galactosyl hydroxylysine and to glucosylgalactosyl hydroxylysine by collagen galactosyltransferase and glucosyltransferase, respectively. The carboxyl termini of three properly hydroxylated procollagen molecules will associate and spontaneously propagate a procollagen triple helix from the carboxyl terminus to the amino terminus. The triple helical procollagen will be transported from the ER to the extracellular space via the Golgi (part c). Two metalloproteinases, a procollagen N-terminal proteinase and a procollagen C-terminal proteinase, cleave the non-helical termini (part d) and the mature collagen proteins spontaneously aggregate to form a collagen fibril (part e). The final step, collagen fibre formation, is initiated by collagen crosslinking, which is catalysed by lysyl oxidase (LOX) family members and occurs via the lysine aldehyde- or hydroxylysine aldehyde-initiated pathway (part f). The number and the proportion of the various crosslinks are tissue specific and are regulated by the steric relationship between localized collagen molecules, the type of collagens co-polymerized and the glycosylation and the hydroxylation of the participating amino acid residues. For example, lysine aldehyde-initiated crosslinks are found in soft connective tissue, in contrast to hydroxylysine aldehyde-initiated crosslinks, which are found in stiff connective tissues. Many non-fibrillar collagens retain a non-collagenous N- or C-terminal, which prevents the spontaneous formation of collagen fibrils, and in these collagens cysteine crosslinks might be the only source of covalent intermolecular bonds. Enzymes highlighted in red are induced under hypoxic conditions. LOXL, LOX-like protein.