Role of TIMPs (tissue inhibitors of metalloproteinases) in pericellular proteolysis: The specificity is in the detail

Gillian Murphy*, Vera Knäuper, Meng Huee Lee, Augustin Amour, Joanna R. Worley, Mike Hutton, Susan Atkinson, Magdalene Rapti, Richard Williamson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

64 Citations (Scopus)


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 MTl-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 α-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.

Original languageEnglish
Pages (from-to)65-80
Number of pages16
JournalBiochemical Society Symposium
Issue number70
Publication statusPublished - 2003
Externally publishedYes

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