The specificity of TIMP-2 for matrix metalloproteinases can be modified by single amino acid mutations

Butler, Georgina S., Hutton, Mike, Wattam, Beth A., Williamson, Richard A., Knauper, Vera ORCID: https://orcid.org/0000-0002-3965-9924, Willenbrock, Frances and Murphy, Gillian 1999. The specificity of TIMP-2 for matrix metalloproteinases can be modified by single amino acid mutations. Journal of Biological Chemistry 274 (29) , pp. 20391-20396. 10.1074/jbc.274.29.20391

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Abstract

Residues 1–127 of human TIMP-2 (N-TIMP-2), comprising three of the disulfide-bonded loops of the TIMP-2 molecule, is a discrete protein domain that folds independently of the C-terminal domain. This domain has been shown to be necessary and sufficient for metalloproteinase inhibition and contains the major sites of interaction with the catalytic N-terminal domain of active matrix metalloproteinases (MMPs). Residues identified as being involved in the interaction with MMPs by NMR chemical shift perturbation studies and TIMP/MMP crystal structures have been altered by site-directed mutagenesis. We show, by measurement of association rates and apparent inhibition constants, that the specificity of these N-TIMP-2 mutants for a range of MMPs can be altered by single site mutations in either the TIMP “ridge” (Cys1–Cys3 and Ser68–Cys72) or the flexible AB loop (Ser31–Ile41). This work demonstrates that it is possible to engineer TIMPs with altered specificity and suggests that this form of protein engineering may be useful in the treatment of diseases such as arthritis and cancer where the selective inhibition of key MMPs is desirable.

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/161590

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