Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, J1H5N4, Canada.
Sci Rep. 2020 Jun 22;10(1):10091. doi: 10.1038/s41598-020-67005-6.
The amyloid beta peptide (Aβ) is derived from the amyloid precursor protein (APP) by secretase processing. APP is also cleaved by numerous other proteases, such as the type II transmembrane serine protease matriptase, with consequences on the production of Aβ. Because the APP homolog protein amyloid-like protein 1 (APLP1) shares similarities with APP, we sought to determine if matriptase also plays a role in its processing. Here, we demonstrate that matriptase directly interacts with APLP1 and that APLP1 is cleaved in cellulo by matriptase in its E1 ectodomains at arginine 124. Replacing Arg124 with Ala abolished APLP1 processing by matriptase. Using a bioluminescence resonance energy transfer (BRET) assay we found that matriptase reduces APLP1 homodimeric interactions. This study identifies matriptase as the first protease cleaving APLP1 in its dimerization domain, potentially altering the multiple functions associated with dimer formation.
淀粉样β肽（Aβ）由淀粉样前体蛋白（APP）经蛋白酶切割产生。APP 还被许多其他蛋白酶切割，如 II 型跨膜丝氨酸蛋白酶组织蛋白酶 H，这会影响 Aβ 的产生。由于 APP 同源蛋白淀粉样蛋白 1（APLP1）与 APP 具有相似性，我们试图确定组织蛋白酶 H 是否也在其加工过程中发挥作用。在这里，我们证明了组织蛋白酶 H 与 APLP1 直接相互作用，并且 APLP1 在细胞内被组织蛋白酶 H 在其 E1 外结构域中的精氨酸 124 切割。用丙氨酸取代 Arg124 可消除 APLP1 被组织蛋白酶 H 的切割。使用生物发光共振能量转移（BRET）测定法，我们发现组织蛋白酶 H 降低了 APLP1 同源二聚体的相互作用。这项研究确定组织蛋白酶 H 是第一个在其二聚化结构域切割 APLP1 的蛋白酶，这可能改变了与二聚体形成相关的多种功能。
