title: The intact Kunitz domain protects the amyloid precursor protein from being processed by matriptase-2.
abstract: Proteolytic processing of the amyloid precursor protein (APP) leads to amyloid-β (Aβ) peptides. So far, the mechanism of APP processing is insufficiently characterized at the molecular level. Whereas the knowledge of Aβ generation by several proteases has been expanded, the contribution of the Kunitz-type protease inhibitor domain (KPI) present in two major APP isoforms to the complex proteolytic processing of APP is poorly understood. In this study, we have identified KPI-containing APP as a very potent, slow-binding inhibitor for the membrane-bound proteolytic regulator of iron homeostasis matriptase-2 by forming stable complexes with its target protease in HEK cells. Inhibition and complex formation depend on the intact KPI domain. By inhibiting matriptase-2, KPI-containing APP is protected from matriptase-2-mediated proteolysis within the Aβ region, thus preventing the generation of N-terminally truncated Aβ.
authors.forename: Anna-Madeleine
authors.initials: AM
authors.lastname: Beckmann
authors.forename: Konstantin
authors.initials: K
authors.lastname: Glebov
authors.forename: Jochen
authors.initials: J
authors.lastname: Walter
authors.forename: Olaf
authors.initials: O
authors.lastname: Merkel
authors.forename: Martin
authors.initials: M
authors.lastname: Mangold
authors.forename: Frederike
authors.initials: F
authors.lastname: Schmidt
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker-Pauly
authors.forename: Michael
authors.initials: M
authors.lastname: Gütschow
authors.forename: Marit
authors.initials: M
authors.lastname: Stirnberg
mesh_terms: D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000032:analysis / Q000378:metabolism*; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D012697:Serine Endopeptidases; C467801:matriptase 2