Full-length and N-TIMP-3 display equal inhibitory activities toward TNF-α convertase

Meng Huee Lee, Vera Knäuper, J. David Becherer, Gillian Murphy

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52 Citations (Scopus)


We previously reported that tumor necrosis factor-α converting enzyme (TACE) was specifically inhibited by TIMP-3 but not TIMP-1, -2, and -4. Further mutagenesis studies showed that the N-terminal domain of TIMP-3 (N-TIMP-3) retained full inhibitory activity towards TACE. Full-length TIMP-3 and N-TIMP-3 exhibited indistinguishable values for the association rate constant and inhibitory affinity constant for the active catalytic domain of TACE (kon∼105M-1s-1and Kiapp∼0.20 nM). Moreover, their kon(∼104M-1s-1) and Kiapp(∼1.0 nM) values with a longer form of TACE (which encompasses the complete ectodomain including disintegrin, EGF and Crambin-like domains) were also shown to be similar. Detailed kinetic analyses indicated that TIMP-3 associated more quickly and with tighter final binding with TACE devoid of these C-terminal domains. We conclude that, unlike the interaction between many MMPs and TIMPs, the C-terminal domains of TIMP-3 and TACE are not essential in the formation of a tight binary complex.

Original languageEnglish
Pages (from-to)945-950
Number of pages6
JournalBiochemical and Biophysical Research Communications
Issue number3
Publication statusPublished - 15 Dec 2001
Externally publishedYes


  • ADAM
  • Metalloproteinase
  • TIMP

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