The amyloid precursor protein/protease nexin 2 Kunitz inhibitor domain is a highly specific substrate of mesotrypsin.

The Journal of Biological Chemistry
Moh'd A SalamehEvette S Radisky

Abstract

The amyloid precursor protein (APP) is a ubiquitously expressed transmembrane adhesion protein and the progenitor of amyloid-beta peptides. The major splice isoforms of APP expressed by most tissues contain a Kunitz protease inhibitor domain; secreted APP containing this domain is also known as protease nexin 2 and potently inhibits serine proteases, including trypsin and coagulation factors. The atypical human trypsin isoform mesotrypsin is resistant to inhibition by most protein protease inhibitors and cleaves some inhibitors at a substantially accelerated rate. Here, in a proteomic screen to identify potential physiological substrates of mesotrypsin, we find that APP/protease nexin 2 is selectively cleaved by mesotrypsin within the Kunitz protease inhibitor domain. In studies employing the recombinant Kunitz domain of APP (APPI), we show that mesotrypsin cleaves selectively at the Arg(15)-Ala(16) reactive site bond, with kinetic constants approaching those of other proteases toward highly specific protein substrates. Finally, we show that cleavage of APPI compromises its inhibition of other serine proteases, including cationic trypsin and factor XIa, by 2 orders of magnitude. Because APP/protease nexin 2 and mesotrypsin are ...Continue Reading

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Citations

Sep 24, 2010·The Journal of Biological Chemistry·Moh'd A SalamehEvette S Radisky
Dec 22, 2012·Molecular Cancer Research : MCR·Alexandra HocklaEvette S Radisky
Jul 18, 2014·Science Translational Medicine·Irina A BuhimschiCatalin S Buhimschi
Oct 16, 2015·Parasitology·Shiwanthi L RanasingheDonald P McManus
May 23, 2012·Protein Science : a Publication of the Protein Society·Moh'd A SalamehEvette S Radisky
Jul 23, 2013·Biochemical and Biophysical Research Communications·Li-Min ChuaBoon-Seng Wong
Jul 16, 2015·The Journal of Biological Chemistry·Alexandre P AlloyEvette S Radisky
Feb 6, 2020·The Journal of Biological Chemistry·Vanda ToldiMiklós Sahin-Tóth
Feb 4, 2016·Oncotarget·Poomy PandeyJoyce C Solheim
May 28, 2015·The Journal of Biological Chemistry·András SzabóMiklós Sahin-Tóth
May 4, 2017·PloS One·Olumide KayodeEvette S Radisky
Nov 5, 2016·The Journal of Biological Chemistry·Olumide KayodeEvette S Radisky
Apr 2, 2016·International Journal of Molecular Medicine·Li-Ping ZhaoMan-Hua Cui
Feb 3, 2021·Pancreatology : Official Journal of the International Association of Pancreatology (IAP) ... [et Al.]·Dóra Mosztbacher, Miklós Sahin-Tóth
Oct 6, 2021·Journal of the American Chemical Society·Michael HeyneJulia M Shifman

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