Beckmann Anna-Madeleine, Glebov Konstantin, Walter Jochen, Merkel Olaf, Mangold Martin, Schmidt Frederike, Becker-Pauly Christoph, Gütschow Michael, Stirnberg Marit
Biol Chem. 2016 Aug 1;397(8):777-90. doi: 10.1515/hsz-2015-0263.
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.
淀粉样前体蛋白（APP）的蛋白水解加工会产生淀粉样β（Aβ）肽。到目前为止，APP加工机制在分子水平上的特征尚不充分。虽然几种蛋白酶产生Aβ的知识有所扩展，但两种主要APP亚型中存在的库尼茨型蛋白酶抑制剂结构域（KPI）对APP复杂蛋白水解加工的贡献却知之甚少。在本研究中，我们已确定含KPI的APP是一种非常有效的、慢结合抑制剂，可通过在HEK细胞中与其靶蛋白酶形成稳定复合物，抑制铁稳态膜结合蛋白水解调节因子matriptase-2。抑制作用和复合物形成取决于完整的KPI结构域。通过抑制matriptase-2，含KPI的APP在Aβ区域内免受matriptase-2介导的蛋白水解作用，从而防止产生N端截短的Aβ。
