期刊
BIOLOGICAL CHEMISTRY
卷 397, 期 8, 页码 777-790出版社
WALTER DE GRUYTER GMBH
DOI: 10.1515/hsz-2015-0263
关键词
amyloid beta; enzyme kinetics; iron homeostasis; Kunitz inhibitor; type II transmembrane serine protease
资金
- German Research Foundation (DFG) [STI 660/1-1]
- Maria von Linden Program of the Gender Equality Center of the University of Bonn
- Collaborative Research Center 'Regulation and manipulation of information flow within dynamic protein and lipid environments' - DFG [SFB 645]
- DFG [SFB 877, BE 4086/2-1]
Proteolytic processing of the amyloid precursor protein (APP) leads to amyloid-beta (A beta) peptides. So far, the mechanism of APP processing is insufficiently characterized at the molecular level. Whereas the knowledge of A beta 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 A beta region, thus preventing the generation of N-terminally truncated A beta.
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