γ-Secretase Inhibitors and Modulators Induce Distinct Conformational Changes in the Active Sites of γ-Secretase and Signal Peptide Peptidase
γ-Secretase Inhibitors and Modulators Induce Distinct Conformational Changes in the Active Sites of γ-Secretase and Signal Peptide Peptidase
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DOI：
10.1021/acschembio.5b00321
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发表时间：
2015-08-01
影响因子：
4
通讯作者：
Li, Yue-Ming
中科院分区：
文献类型：
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作者：
Gertsik, Natalya;Chau, De-Ming;Li, Yue-Ming
γ-分泌酶抑制剂（GSI）和调节剂（GSM）分别处于癌症和阿尔茨海默病研究的前沿。虽然两者都有治疗前景，但对它们与γ分泌酶以外的蛋白质的相互作用知之甚少。信号肽肽酶（SPP），像γ-分泌酶一样，是一种多跨膜乙酰化蛋白酶，催化调节的膜内蛋白水解。我们使用活性位点定向的探针研究了不同GSI和GSMs对γ-分泌酶和SPP活性位点的影响，发现非过渡态GSI抑制活性探针对γ-分泌酶的标记，但增强SPP的标记。GSMs的情况正好相反，它对γ-分泌酶的标记几乎没有影响，但减少了SPP的标记。这些结果表明，GSI和GSM不仅改变了γ-分泌酶的结构，而且改变了SPP的结构，导致酶活性和特异性的潜在变化，可能影响这些分子的临床结果。
gamma-Secretase inhibitors (GSIs) and modulators (GSMs) are at the frontline of cancer and Alzheimer's disease research, respectively. While both are therapeutically promising, not much is known about their interactions with proteins other than gamma-secretase. Signal peptide peptidase (SPP), like gamma-secretase, is a multispan transmembrane aspartyl protease that catalyzes regulated intramembrane proteolysis. We used active site-directed photophore walking probes to study the effects of different GSIs and GSMs on the active sites of gamma-secretase and SPP and found that nontransition state GSIs inhibit labeling of gamma-secretase by activity-based probes but enhance labeling of SPP. The opposite is true of GSMs, which have little effect on the labeling of gamma-secretase but diminish labeling of SPP. These results demonstrate that GSIs and GSMs are altering the structure of not only gamma-secretase but also SPP, leading to potential changes in enzyme activity and specificity that may impact the clinical outcomes of these molecules.