The role of the C-terminal domain of human collagenase-3 (MMP-13) in the activation of procollagenase-3, substrate specificity, and tissue inhibitor of metalloproteinase interaction

Knauper, Vera ORCID: https://orcid.org/0000-0002-3965-9924, Cowell, Susan, Smith, Bryan, López-Otin, Carlos, O'Shea, Mark, Morris, Helen, Zardi, Luciano and Murphy, Gillian 1997. The role of the C-terminal domain of human collagenase-3 (MMP-13) in the activation of procollagenase-3, substrate specificity, and tissue inhibitor of metalloproteinase interaction. Journal of Biological Chemistry 272 (12) , pp. 7608-7616. 10.1074/jbc.272.12.7608

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Abstract

Recombinant human procollagenase-3 and a C-terminal truncated form (Δ249-451 procollagenase-3) have been stably expressed in myeloma cells and purified. The truncated proenzyme could be processed by aminophenylmercuric acetate via a short-lived intermediate form (N-terminal Leu58) to the final active form (N-terminal Tyr85). The kinetics of activation were not affected by removal of the hemopexin-like C-terminal domain. The specific activities of both collagenase-3 and Δ249-451 collagenase-3 were found to be similar using two quenched fluorescent substrates, but Δ249-451 collagenase-3 failed to cleave native triple helical collagens (types I and II) into characteristic one- and three-quarter fragments. It was noted, however, that the β1,2(I) chains of type I collagen were susceptible to Δ249-451 collagenase-3, which indicates that the catalytic domain displays telopeptidase activity, thereby generating α1,2(I) chains that are slightly shorter than those in native type I collagen. It can be concluded that the C-terminal domain is only essential for the triple helicase activity of collagenase-3. Binding of procollagenase-3 and active collagenase-3 to type I collagen is mediated by the C-terminal domain. Both collagenase-3 and Δ249-451 collagenase-3 hydrolyzed the large tenascin C isoform, fibronectin, recombinant fibronectin fragments, and type IV, IX, X, and XIV collagens; thus, these events were independent from C-terminal domain interactions. In contrast, the minor cartilage type XI collagen was resistant to cleavage. Kinetic analysis of the mechanism of inhibition of wild-type and Δ249-451 collagenase-3 by wild-type and mutant tissue inhibitors of metalloproteinase (TIMPs) revealed that the association rates for complex formation were influenced by both N- and C-terminal domain interactions. The C-terminal domain of wild-type collagenase-3 promoted increased association rates with the full-length inhibitors TIMP-1 and TIMP-3 and the hybrid N.TIMP-2/C.TIMP-1 by a factor of up to 33. In contrast, the association rates for complex formation with TIMP-2 and N.TIMP-1/C.TIMP-2 were only marginally affected by C-terminal domain interactions.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Dentistry
Publisher:	Elsevier
ISSN:	0021-9258
Last Modified:	11 Sep 2023 09:33
URI:	https://orca.cardiff.ac.uk/id/eprint/161602

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