Abstract
In many embryonic tissues, type IIA procollagen is synthesized and deposited into the extracellular matrix containing the NH(2)-propeptide, the cysteine-rich domain of which binds to bone morphogenic proteins. To investigate whether matrix metalloproteinases (MMPs) synthesized during development and disease can cleave the NH(2) terminus of type II procollagens, we tested eight types of enzymes. Recombinant trimeric type IIA collagen NH(2)-propeptide encoded by exons 1-8 fused to the lectin domain of rat surfactant protein D was used as a substrate. The latter allowed trimerization of the propeptide domain and permitted isolation by saccharide affinity chromatography. Although MMPs 1, 2, and 8 did not show cleavage, MMPs 3, 7, 9, 13, and 14 cleaved the recombinant protein both at the telopeptide region and at the procollagen N-proteinase cleavage site. MMPs 7 and 13 demonstrated other cleavage sites in the type II collagen-specific region of the N-propeptide; MMP-7 had another cleavage site close to the COOH terminus of the cysteine-rich domain. To prove that an MMP can cleave the native type IIA procollagen in situ, we demonstrated that MMP-7 removes the NH(2)-propeptide from collagen fibrils in the extracellular matrix of fetal cartilage and identified the cleavage products. Because the N-proteinase and telopeptidase cleavage sites are present in both type IIA and type IIB procollagens and the telopeptide cleavage site is retained in the mature collagen fibril, this processing could be important to type IIB procollagen and to mature collagen fibrils as well.
Highlights
Fibrillar collagen types I, II, III, and V are synthesized with globular propeptides at both the COOH and NH2 termini that are generally removed prior to formation of fibrils
To prove that an matrix metalloproteinases (MMPs) can cleave the native type IIA procollagen in situ, we demonstrated that MMP-7 removes the NH2-propeptide from collagen fibrils in the extracellular matrix of fetal cartilage and identified the cleavage products
Because rat surfactant protein D (SPD) was resistant to MMP cleavage, we inferred that cleavage of IIA-SPD occurred within the procollagen domain
Summary
Fibrillar collagen types I, II, III, and V are synthesized with globular propeptides at both the COOH and NH2 termini that are generally removed prior to formation of fibrils. We have shown recently that the cysteine-rich domain of type IIA procollagen NH2-propeptide binds to members of the TGF- superfamily, TGF-1 and BMP-2, thereby predicting an important function for the NH2-propeptide in the extracellular matrix [3]. Chordin and sog are homologues containing the same cysteine-rich domain as the collagen NH2-propeptide and bind to BMP-4 and decapentaplegic, respectively [14, 15]. The type IIA pN-procollagen containing the cysteine-rich domain is deposited in the extracellular matrix providing potential localization of BMP in the insoluble compartment of the extracellular matrix. Enzymic Processing of the Fibrillar Collagen N-propeptide cleave in the type II-specific minor helix and MMP-7 cleaves in the type IIA-specific cysteine-rich domain
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