Proteinases of the Bone Morphogenetic Protein-1 Family Convert Procollagen VII to Mature Anchoring Fibril Collagen

Abstract

Collagen VII is the major structural component of the anchoring fibrils at the dermal-epidermal junction in the skin. It is secreted by keratinocytes as a precursor, procollagen VII, and processed into mature collagen during polymerization of the anchoring fibrils. We show that bone morphogenetic protein-1 (BMP-1), which exhibits procollagen C-proteinase activity, cleaves the Cterminal propeptide from human procollagen VII. The cleavage occurs at the BMP-1 consensus cleavage site SYAA2DTAG within the NC-2 domain. Mammalian tolloid-like (mTLL)-1 and -2, two other proteases of the astacin enzyme family, were able to process procollagen VII at the same site in vitro. Immunohistochemical and genetic evidence supported the involvement of these enzymes in cleaving type VII procollagen in vivo. Both BMP-1 and mTLL-1 are expressed in the skin and in cultured cutaneous cells. A naturally occurring deletion in the human COL7A1 gene, 8523del14, which is associated with dystrophic epidermolysis bullosa and eliminates the BMP-1 consensus sequence, abolished processing of procollagen VII, and in mutant skin procollagen VII accumulated at the dermal-epidermal junction. On the other hand, deficiency of BMP-1 in the skin of knockout mouse embryos did not prevent processing of procollagen VII to mature collagen, suggesting that mTLL-1 and/or mTLL-2 can substitute for BMP-1 in the processing of procollagen VII in situ.

Survival impact of psammoma body, stromal calcification, and bone formation in papillary thyroid carcinoma

“…8 BMP-1 is a kind of metalloproteinase with conserved domains, and can convert a variety of precursor proteins into mature or active forms that are involved in extracellular matrix formation. 12,13,27,28 It is BMP-1 that converts procollagen types I-III and VII into their mature forms and mediates C-terminal processing of procollagen V homotrimer. 13,27,28 We noted an increased expression of BMP-1 in carcinoma tissues with psammoma bodies or with stromal calcification, which confirms the hypothesized role of BMP-1 in calcification and reveals a possible new role for BMP-1 in the formation of psammoma bodies.…”

“…12,13,27,28 It is BMP-1 that converts procollagen types I-III and VII into their mature forms and mediates C-terminal processing of procollagen V homotrimer. 13,27,28 We noted an increased expression of BMP-1 in carcinoma tissues with psammoma bodies or with stromal calcification, which confirms the hypothesized role of BMP-1 in calcification and reveals a possible new role for BMP-1 in the formation of psammoma bodies. We examined the frequency of PBS in 229 cases of papillary thyroid carcinoma and investigated its clinical significance and survival impact.…”

The bone morphogenetic protein 1/Tolloid-like metalloproteinases

“…3 and 4). In vitro cleavage assays have confirmed that BMP1, mTLL1 and mTLL2 are capable of cleaving the NC2 domain (Rattenholl et al, 2002), however type VII collagen appears to be fully processed in the skin of mouse embryos null for the Bmp1 gene, which encodes both BMP1 and mTLD (Rattenholl et al, 2002). Thus, mTLL1 and mTLL2 may fully compensate for loss of Bmp1 in these mice, for removal of the procollagen VII NC2 domain.…”

Post-translational Modification of Bone Morphogenetic Protein-1 Is Required for Secretion and Stability of the Protein

“…BMP-1, mammalian tolloid, and two highly homologous relatives tolloid-like 1 and 2 constitute the tolloid clade of astacin-like metalloproteinases that have important functions in development and extracellular matrix formation (2). BMP-1 cleaves fibrillar procollagen type I, II, III (3,4), and V (5-7), as well as type VII procollagen (8), prolysyl oxidase (9), probiglycan (10), and the ␥2 chain of prolaminin 5 (11). BMP-1 also cleaves chordin (2) therefore affecting dorsal-ventral patterning in vertebrates (12).…”