Characterization of the AB loop region of TIMP-2. Involvement in pro-MMP-2 activation.

Rapti, M. and Knauper, V. and Murphy, G. and Williamson, R.A. (2006) Characterization of the AB loop region of TIMP-2. Involvement in pro-MMP-2 activation. Journal of Biological Chemistry, 281 . pp. 23386-23394. (Access to this publication is restricted)

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Abstract

Tissue inhibitor of metalloproteinases-2 (TIMP-2) is unique as it is the only member of the TIMP family that is involved in the cellular activation of promatrix metalloproteinase-2 (pro-MMP-2) by virtue of forming a trimolecular complex with membrane type 1 matrix metalloproteinase (MT1-MMP) on the cell surface. TIMP-4 is similar in structure to TIMP-2 but is unable to support the activation of the proenzyme. Several reports have highlighted the importance of the TIMP-2 C-terminal domain in the pro-MMP-2 activation complex; however, very little is known about the role of the extended AB loop of TIMP-2 in this mechanism even though it has been shown to interact with MT1-MMP. In this study we show by mutagenesis and kinetic analysis that it is possible to transfer the MT1-MMP binding affinity of the TIMP-2 AB loop to TIMP-4 but that its transplantation into TIMP-4 does not endow the inhibitor with pro-MMP-2 activating activity. However, transfer of both the AB loop and C-terminal domain of TIMP-2 to TIMP-4 generates a mutant that can activate pro-MMP-2 and so demonstrates that both these regions of TIMP-2 are important for the activation process.

Item Type: Article
Subjects: Q Science
Divisions: Faculties > Science Technology and Medical Studies > School of Biosciences > Protein Science Group
Depositing User: Sue Davies
Date Deposited: 19 Dec 2007 17:54
Last Modified: 05 Sep 2011 23:19
Resource URI: http://kar.kent.ac.uk/id/eprint/76 (The current URI for this page, for reference purposes)
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