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Inhibition of γ-secretase activity by a monoclonal antibody against the extracellular hydrophilic loop of presenilin 1

机译：抗早老素1细胞外亲水环的单克隆抗体抑制γ-分泌酶的活性

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摘要

Presenilin 1 (PS1) comprises a catalytic subunit of γ-secretase, which is an intramembrane-cleaving protease responsible for generation of amyloid-β peptides as well as Notch cleavage, the latter being implicated in cancer. We have shown that transmembrane domains (TMDs) 1, 6, 7, and 9 of PS1 form the "catalytic pore" structure within the membrane for intramembrane proteolysis. Here we report a novel monoclonal antibody 9D11, which directly recognizes the TMD1-proximal residues in the hydrophilic loop region. Intriguingly, 9D11 inhibited the γ-secretase activity irrespective of the binding of known γ-secretase inhibitors and abolished Notch signaling-dependent cancer cell viability. Our data suggest that the juxtamembrane region of TMD1 of PS1 is a novel molecular target for the mechanism-based inhibition of γ-secretase and the development of the anticancer drug.
机译：早老素1（PS1）包含一个γ-分泌酶的催化亚基，它是一种膜内切割蛋白酶，负责生成淀粉样β肽以及Notch裂解，后者与癌症有关。我们已经显示PS1的跨膜域（TMD）1，6，7和9形成膜内膜内蛋白水解的“催化孔”结构。在这里，我们报告一种新型的单克隆抗体9D11，它直接识别亲水环区域中的TMD1近端残基。有趣的是，9D11抑制γ-分泌酶的活性，而与已知的γ-分泌酶抑制剂的结合无关，并且废除了Notch信号依赖性癌细胞的生存能力。我们的数据表明PS1的TMD1的近膜区域是基于机制的γ-分泌酶抑制和抗癌药物开发的新型分子靶标。

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