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

Lee, Meng-Huee, Knauper, Vera ORCID: https://orcid.org/0000-0002-3965-9924, Becherer, J.David and Murphy, Gillian 2001. Full-length and N-TIMP-3 display equal inhibitory activities toward TNF-α convertase. Biochemical and Biophysical Research Communications 280 (3) , pp. 945-950. 10.1006/bbrc.2000.4192

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Abstract

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 ∼105 M−1 s−1 and Kappi ∼0.20 nM). Moreover, their kon (∼104 M−1 s−1) and Kappi (∼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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Dentistry
Publisher:	Elsevier
ISSN:	0006-291X
Last Modified:	14 Sep 2023 15:49
URI:	https://orca.cardiff.ac.uk/id/eprint/161619

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