Identification of key sequence determinants for the inhibitory function of the prodomain of TACE

Biochemistry
Patricia E GonzalesMarcos E Milla

Abstract

The TNFalpha converting enzyme (TACE) is a zinc metalloproteinase that mediates shedding of multiple cell surface proteins. Regulation of TACE enzymatic activity is ultimately mediated via proteolytic removal of its inhibitory prodomain. Sequence determinants for TACE prodomain inhibition of the catalytic domain are yet to be identified. Surprisingly, although TACE and ADAM 10 (closest homologue) share only 23% sequence identity at their prodomains, the latter in isolation inhibits TACE with the same potency as TACE own prodomain. In contrast, the prodomain of ADAM 9 inhibited TACE only weakly. Detailed analysis of ADAM prodomains revealed two short regions for which TACE and ADAM 10 depart dramatically from all other family members. We prepared TACE prodomain variants containing full or partial switches to ADAM 9 residues at those two regions and examined their functional properties. Variants containing ADAM 9 substitutions including amino acid residues 72-82 and 126-137 were fully inactive for TACE inhibition. A third variant comprising residues 114-125 was active but at lower potency relative to wild type. All inactive variants appeared to be correctly folded. Finally, the amino acid residue Phe72 and the motif Asp-Asp-Val-I...Continue Reading

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Citations

Sep 25, 2010·Journal of Molecular Graphics & Modelling·Eamonn F HealyGunnar Lindfors
Jul 30, 2010·International Journal of Experimental Pathology·Gillian Murphy
Oct 20, 2009·Drug Discovery Today·Malú G Tansey, David E Szymkowski
Jan 15, 2011·Proceedings of the National Academy of Sciences of the United States of America·Theodoros GoulasF Xavier Gomis-Rüth
Feb 27, 2010·Critical Reviews in Biochemistry and Molecular Biology·Monika Gooz
Oct 15, 2013·The Journal of Biological Chemistry·Katja Möller-HackbarthJürgen Scheller
Aug 30, 2018·Cell Death & Disease·Noelia Geribaldi-DoldánCarmen Castro

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