The Metalloprotease Meprin β Generates Amino Terminal-truncated Amyloid β Peptide Species
The Metalloprotease Meprin β Generates Amino Terminal-truncated Amyloid β Peptide Species
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DOI：
10.1074/jbc.m112.395608
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发表时间：
2012-09-28
影响因子：
4.8
通讯作者：
Pietrzik, Claus U.
中科院分区：
文献类型：
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作者：
Bien, Jessica;Jefferson, Tamara;Pietrzik, Claus U.
淀粉样β (Aβ) 肽在阿尔茨海默病患者的大脑中大量存在，是该疾病发病机制的核心。因此，了解淀粉样前体蛋白（APP）的加工过程至关重要。最近，我们证明金属蛋白酶 meprin beta 可裂解 APP 并释放可溶性 N 端 APP (N-APP) 片段。在这项工作中，我们提供的证据表明 meprin beta 也可以以类似于 β 分泌酶的方式处理 APP。我们在野生型和 APP 瑞典突变体的淀粉样蛋白 β 序列中在位置 p1 和 p2 处鉴定了 meprin β 的切割位点，从而产生从第一个或第二个氨基酸残基开始的 Aβ 变体。对于野生型和瑞典突变体 APP 形式，我们观察到 meprin beta 的动力学值甚至比 BACE1 更高。在没有 BACE1/2 活性的情况下，使用 β 分泌酶抑制剂和 BACE 敲除细胞也观察到了 meprin β 对 APP 和 A β 生成的酶活性，表明 meprin β 的作用独立于 β 分泌酶。
The amyloid beta (A beta) peptide, which is abundantly found in the brains of patients suffering from Alzheimer disease, is central in the pathogenesis of this disease. Therefore, to understand the processing of the amyloid precursor protein (APP) is of critical importance. Recently, we demonstrated that the metalloprotease meprin beta cleaves APP and liberates soluble N-terminal APP (N-APP) fragments. In this work, we present evidence that meprin beta can also process APP in a manner reminiscent of beta-secretase. We identified cleavage sites of meprin beta in the amyloid beta sequence of the wild type and Swedish mutant of APP at positions p1 and p2, thereby generating A beta variants starting at the first or second amino acid residue. We observed even higher kinetic values for meprin beta than BACE1 for both the wild type and the Swedish mutant APP form. This enzymatic activity of meprin beta on APP and A beta generation was also observed in the absence of BACE1/2 activity using a beta-secretase inhibitor and BACE knock-out cells, indicating that meprin beta acts independently of beta-secretase.