Reactive-site mutants of N-TIMP-3 that selectively inhibit ADAMTS-4 and ADAMTS-5: biological and structural implications.

The Biochemical Journal
Ngee Han LimHideaki Nagase

Abstract

We have reported previously that reactive-site mutants of N-TIMP-3 [N-terminal inhibitory domain of TIMP-3 (tissue inhibitor of metalloproteinases 3)] modified at the N-terminus, selectively inhibited ADAM17 (a disintegrin and metalloproteinase 17) over the MMPs (matrix metalloproteinases). The primary aggrecanases ADAMTS (ADAM with thrombospondin motifs) -4 and -5 are ADAM17-related metalloproteinases which are similarly inhibited by TIMP-3, but are poorly inhibited by other TIMPs. Using a newly developed recombinant protein substrate based on the IGD (interglobular domain) of aggrecan, gst-IGD-flag, these reactive-site mutants were found to similarly inhibit ADAMTS-4 and ADAMTS-5. Further mutations of N-TIMP-3 indicated that up to two extra alanine residues can be attached to the N-terminus before the Ki (app) for ADAMTS-4 and ADAMTS-5 increased to over 100 nM. No other residues tested at the [-1] position produced inhibitors as potent as the alanine mutant. The mutants N-TIMP-3(T2G), [-1A]N-TIMP-3 and [-2A]N-TIMP-3 were effective inhibitors of aggrecan degradation, but not of collagen degradation in both IL-1α (interleukin-1α)-stimulated porcine articular cartilage explants and IL-1α with oncostatin M-stimulated human cartil...Continue Reading

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Citations

Oct 26, 2012·The Journal of Biological Chemistry·Vladislav S Golubkov, Alex Y Strongin
Jun 19, 2012·The Journal of Biological Chemistry·Weiqiang GaoJ Evan Sadler
Oct 16, 2012·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Kazuhiro YamamotoHideaki Nagase
Nov 2, 2013·Journal of Neuroinflammation·Sighild LemarchantJari Koistinaho
Mar 3, 2012·Journal of the American Society of Nephrology : JASN·Claudia SchrimpfJeremy S Duffield
Feb 12, 2013·The Journal of Biological Chemistry·Shouichi HigashiKaoru Miyazaki
Oct 7, 2015·Journal of Orthopaedic Surgery and Research·Zhongyi SunJiwei Tian
Jul 23, 2011·Biochimica Et Biophysica Acta·Linda Troeberg, Hideaki Nagase
Apr 12, 2015·Matrix Biology : Journal of the International Society for Matrix Biology·Mourad Bekhouche, Alain Colige
May 31, 2015·Genome Biology·Richard KelwickDylan R Edwards
Nov 3, 2015·Journal of Molecular and Cellular Cardiology·Pu ZhangZamaneh Kassiri
Mar 5, 2019·F1000Research·David A YoungDavid J Wilkinson
Aug 26, 2015·The Biochemical Journal·Salvatore SantamariaHideaki Nagase
Nov 20, 2018·Journal of Cellular and Molecular Medicine·Ben M AlbertsLisa M Mullen
Jan 3, 2020·Clinical & Experimental Metastasis·Geetanjali P Rai, Sarah K Baird
Aug 11, 2020·Calcified Tissue International·Kazuhiro YamamotoGeorge Bou-Gharios
Feb 14, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Matteo CalligarisSimone Dario Scilabra
Jul 17, 2021·Frontiers in Molecular Biosciences·Keron W J RoseDirk Hubmacher

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BETA
PCR
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size-exclusion chromatography

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Phoretix
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1D
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