Murphy, G. and Knauper, V. and Lee, M.H. and Amour, A. and Worley, J.R. and Hutton, M. and Atkinson, S. and Rapti, M. and Williamson, R.A. (2003) Role of TIMPs (tissue inhibitors of metalloproteinases) in pericellular proteolysis: the specificity is in the detail. Biochem Soc Symp, 70 . pp. 65-80. ISSN 0067-8694.
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Pericellular proteolysis represents one of the key modes by which the cell can modulate its environment, involving not only turnover of the extracellular matrix but also the regulation of cell membrane proteins, such as growth factors and their receptors. The metzincins are active players in such proteolytic events, and their mode of regulation is therefore of particular interest and importance. The TIMPs (tissue inhibitors of metalloproteinases) are established endogenous inhibitors of the matrix metalloproteinases (MMPs), and some have intriguing abilities to associate with the pericellular environment. It has been shown that TIMP-2 can bind to cell surface MT1-MMP (membrane-type 1 MMP) to act as a 'receptor' for proMMP-2 (progelatinase A), such that the latter can be activated efficiently in a localized fashion. We have examined the key structural features of TIMP-2 that determine this unique function, showing that Tyr36 and Glu192-Asp193 are vital for specific interactions with MT1-MMP and proMMP-2 respectively, and hence activation of proMMP-2. TIMP-3 is sequestered at the cell surface by association with the glycosaminoglycan chains of proteoglycans, especially heparan sulphate, and we have shown that it may play a role in the regulation of some ADAMs (a disintegrin and metalloproteinases), including tumour necrosis factor alpha-converting enzyme (TACE; ADAM17). We have established that key residues in TIMP-3 determine its interaction with TACE. Further studies of the features of TIMP-3 that determine specific binding to both ADAM and glycosaminoglycan are required in order to understand these unique properties.
|Additional information:||0067-8694 (Print) Journal Article Research Support, Non-U.S. Gov't Review|
|Uncontrolled keywords:||Amino Acid Sequence Enzyme Activation Hydrolysis Kinetics Matrix Metalloproteinases/*metabolism Molecular Sequence Data Sequence Homology, Amino Acid Substrate Specificity Tissue Inhibitor of Metalloproteinases/chemistry/*physiology|
|Divisions:||Faculties > Science Technology and Medical Studies > School of Biosciences > Protein Science Group|
|Depositing User:||Richard Williamson|
|Date Deposited:||09 Sep 2008 03:47|
|Last Modified:||14 Jan 2010 14:20|
|Resource URI:||http://kar.kent.ac.uk/id/eprint/5312 (The current URI for this page, for reference purposes)|
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