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Localization of the Functional Domains of Human Tissue Inhibitor of Metalloproteinases-3 and the Effects of a Sorsby's Fundus Dystrophy Mutation

Langton, K.P., Barker, M.D. and McKie, N. (1998) Localization of the Functional Domains of Human Tissue Inhibitor of Metalloproteinases-3 and the Effects of a Sorsby's Fundus Dystrophy Mutation. Journal of Biological Chemistry, 273 (27). pp. 16778-16781. ISSN 0021-9258


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A transient COS-7 cell expression system was used to investigate the functional domain arrangement of tissue inhibitor of metalloproteinases-3 (TIMP-3), specifically to assess the contribution of the amino- and carboxylterminal domains of the molecule to its matrix metalloproteinase (MMP) inhibitory and extracellular matrix (ECM) binding properties. Wild type TIMP-3 was entirely localized to the ECM in both its glycosylated (27 kDa) and unglycosylated (24 kDa) forms. A COOH-terminally truncated TIMP-3 molecule was found to be a non- ECM bound MMP inhibitor, whereas a chimeric TIMP molecule, consisting of the NH2-terminal domain of TIMP-2 fused to the COOH-terminal domain of TIMP-3, displayed ECM binding, albeit with a lower affinity than the wild type TIMP-3 molecule. Thus the functional domain arrangement of TIMP-3 is analogous to that seen in TIMP-1 and -2, namely that the NH2-terminal domain is responsible for MMP inhibition whereas the COOH-terminal domain is most important in mediating the specific functions of the molecule. A mutant TIMP-3 in which serine 181 was changed to a cysteine, found in Sorsby’s fundus dystrophy, a hereditary macular degenerative disease, was also expressed in COS-7 cells. This gave rise to an additional 48-kDa species (possibly a TIMP-3 dimer) that retained its ability to inhibit MMPs and localize to the ECM. These data favor the hypothesis that the TIMP-3 mutations seen in Sorsby’s fundus dystrophy contribute to disease progression by accumulation of mutant protein rather than by the loss of functional TIMP-3.

Item Type: Article
Copyright, Publisher and Additional Information: © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
Institution: The University of Sheffield
Academic Units: The University of Sheffield > University of Sheffield Research Centres and Institutes > The Krebs Institute for Biomolecular Research (Sheffield)
The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology (Sheffield)
Depositing User: Sherpa Assistant
Date Deposited: 06 May 2005
Last Modified: 05 Jun 2014 07:59
Published Version: http://www.jbc.org/cgi/content/full/273/27/16778/
Status: Published
Refereed: Yes
URI: http://eprints.whiterose.ac.uk/id/eprint/440

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