Procollagen-peptidases

The procollagen precursors of fibrillar collagens have been known since the 1970s. It became clear that the connective tissue must contain proteolytic activities that cleave the N- and C-propeptides from the procollagens. However, the isolation and characterization of the enzymatic activities proved to be unexpectedly difficult. Both proteinases are large and are synthesized in different forms with polypeptide chains ranging in size from 70 kDa to about 130 kDa.

Procollagen peptidases are enzymes that play an important role in the processing of collagen. The peptidases separate specific propeptides from procollagen molecules, converting soluble procollagen into insoluble collagen, which is then organized into fibrils.

There are 2 main types of procollagen peptidases:

• Procollagen N-peptidase: this enzyme removes the terminal procollagen propetide region
• Procollagen C-peptidase: This enzyme removes the C-terminal propetide region.

Both the procollagen N-proteinase and the procollagen C-proteinase belong to a family of Zn2+-dependent metalloproteinases M12. The N-proteinase exists in two splice variants in a longer form of 140 kDa (pNP1) and a shorter form of 70 kDa (pNP-2).

Both cleave the N-propeptides of procollagen type I and II, but only in the native state, so that the N-telopeptide remains in the hairpin loop configuration. The N-proteinase is a structural homolog to atrolysin and adamalysin II and contains an RGD sequence and properdin-like repeats in the C-terminal part.

The procollagen C-proteinase cleaves the C-propeptides of collagen types I, II and III as well as laminin 5 and the precursor of lysyl oxidase. This enzyme is partially identical to Bone Morphogenetic Protein 1 (BMP-1) or mouse Tolloid Protease and is related to Drosophila Tolloid, Astacin and BP10. All these enzymes share the Zn2+-binding proteinase domain. The cleaved C-terminal propeptides remain in the tissue for some time. This has been demonstrated in particular for type II collagen: the C-propeptide was isolated from cartilage as an intact, disulfide-linked unit, which was given the name chondrocalcin because it is found in calcified cartilage in particular.

In addition to the BMP-1-type C-proteinases described above, other proteinases also appear to be able to cleave procollagen propeptides, e.g. cathepsin D. Mutations in the genes coding for these enzymes (ADAMS2 gene coding for procollagen N-peptidase/BMP1 gene coding for procollagen N-peptidase) can lead to diseases such as Ehlers-Danlos syndrome or osteogenesis imperfecta, as the structural integrity of the collagen is disrupted.

1. Prockop DJ et al. (1998) Procollagen N-proteinase and procollagen C-proteinase. Two unusual metalloproteinases that are essential for procollagen processing probably have important roles in development and cell signaling. Matrix Biol 16:399-408.