Inhibition of g-secretase activity by a monoclonal antibody against the extracellular hydrophilic loop of presenilin 1
Inhibition of g-secretase activity by a monoclonal antibody against the extracellular hydrophilic loop of presenilin 1
复制标题
针对早老素 1 细胞外亲水环的单克隆抗体抑制 g 分泌酶活性
DOI：
10.1021/bi301252r
复制
发表时间：
2013
期刊：
影响因子：
2.9
通讯作者：
Shizuka Takagi-Niidome
中科院分区：
文献类型：
--
作者：
Helmy;M.; Sugiyama;N.; Tomita;M.; Ishihama;Y.;Y. Ogra and Y. Anan;Shizuka Takagi-Niidome
早老素1 （PS1）包含γ-分泌酶的催化亚基，γ-分泌酶是一种膜内切割蛋白酶，负责产生淀粉样蛋白-β肽和Notch切割，后者与癌症有关。我们已经证明，PS1的跨膜结构域（TMDs） 1、6、7和9在膜内形成“催化孔”结构，用于膜内蛋白水解。在这里，我们报道了一种新的单克隆抗体9D11，它直接识别亲水性环区域的tmd1近端残基。有趣的是，无论是否结合已知的γ-分泌酶抑制剂，9D11都能抑制γ-分泌酶的活性，并消除Notch信号依赖性癌细胞的活力。我们的数据表明，PS1的TMD1近膜区是基于机制抑制γ-分泌酶和开发抗癌药物的新分子靶点。
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.