Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides.
Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides.
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DOI：
10.1016/j.jbc.2021.100393
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Selkoe DJ
中科院分区：
文献类型：
--
作者：
Liu L;Lauro BM;Wolfe MS;Selkoe DJ
γ-分泌酶负责将淀粉样前体蛋白（APP）蛋白水解成淀粉样β（Aβ）肽，其在阿尔茨海默病（AD）的发病机制中起中心作用。γ-分泌酶如何调节加工的生化机制，特别是酶与底物之间的相互作用，在很大程度上仍然未知。在这里，诱变揭示了早老素-1（PS1）的亲水性环-1（HL-1）对于γ-分泌酶逐步切割（持续合成能力）和杂环γ-调节化合物对其的变构调节都是至关重要的。HL-1的系统性诱变，包括其所有家族性AD突变和其他工程变体，以及所得Aβ产物的定量显示HL-1对于适当的连续γ-分泌酶持续合成能力是必需的。我们确定HL-1中的Y106、L113和Y115是杂环γ-分泌酶调节剂（GSMs）刺激致病性Aβ肽加工的关键靶点。此外，我们证实APP跨膜区中的GxxxG结构域作为γ-分泌酶持续合成能力的关键底物基序发挥作用：APP-C99中的G29 A取代模拟了GSM的有益作用。总之，这些发现为酶和底物对γ-持续合成能力的结构调节提供了分子基础，促进了降低AD起始淀粉样Aβ肽的新GSM的合理设计。
γ-Secretase is responsible for the proteolysis of amyloid precursor protein (APP) into amyloid-beta (Aβ) peptides, which are centrally implicated in the pathogenesis of Alzheimer’s disease (AD). The biochemical mechanism of how processing by γ-secretase is regulated, especially as regards the interaction between enzyme and substrate, remains largely unknown. Here, mutagenesis reveals that the hydrophilic loop-1 (HL-1) of presenilin-1 (PS1) is critical for both γ-secretase step-wise cleavages (processivity) and its allosteric modulation by heterocyclic γ-modulatory compounds. Systematic mutagenesis of HL-1, including all of its familial AD mutations and additional engineered variants, and quantification of the resultant Aβ products show that HL-1 is necessary for proper sequential γ-secretase processivity. We identify Y106, L113, and Y115 in HL-1 as key targets for heterocyclic γ-secretase modulators (GSMs) to stimulate processing of pathogenic Aβ peptides. Further, we confirm that the GxxxG domain in the APP transmembrane region functions as a critical substrate motif for γ-secretase processivity: a G29A substitution in APP-C99 mimics the beneficial effects of GSMs. Together, these findings provide a molecular basis for the structural regulation of γ-processivity by enzyme and substrate, facilitating the rational design of new GSMs that lower AD-initiating amyloidogenic Aβ peptides.
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