Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH
Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH
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古细菌早老素同源物 PSH 对淀粉样前体蛋白的裂解
DOI：
10.1073/pnas.1502150112
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发表时间：
2015-03-17
影响因子：
11.1
通讯作者：
Shi, Yigong
中科院分区：
文献类型：
--
作者：
Dang, Shangyu;Wu, Shenjie;Shi, Yigong
γ-分泌酶对淀粉样前体蛋白 (APP) 的异常切割会导致阿尔茨海默病的发生。早老素（γ-分泌酶的催化亚基）中已鉴定出 200 多种疾病衍生的突变，这使得调节γ-分泌酶活性成为一个潜在的有吸引力的治疗机会。不幸的是，处理完整的γ-分泌酶的技术挑战阻碍了调节剂的发现，并需要一种方便的替代方法。在这里，我们报道，与γ-分泌酶类似，古细菌早老素同源物PSH忠实地将底物APP C99加工成Aβ42、Aβ40和Aβ38。PSH裂解产物Aβ42与Aβ40的摩尔比与γ-分泌酶几乎相同。 PSH 的蛋白水解活性被早老素特异性抑制剂特异性抑制。已知的γ-分泌酶调节剂也在Aβ42/Aβ40比率方面类似地调节PSH。结构分析揭示了一种已知的 γ-分泌酶抑制剂与 PSH 在其两个催化天冬氨酸残基之间的关联。这些发现将 PSH 确定为替代蛋白酶，用于筛选可调节蛋白酶活性和 γ-分泌酶裂解偏好的试剂。
Aberrant cleavage of amyloid precursor protein (APP) by gamma-secretase contributes to the development of Alzheimer's disease. More than 200 disease-derived mutations have been identified in presenilin (the catalytic subunit of gamma-secretase), making modulation of gamma-secretase activity a potentially attractive therapeutic opportunity. Unfortunately, the technical challenges in dealing with intact gamma-secretase have hindered discovery of modulators and demand a convenient substitute approach. Here we report that, similar to gamma-secretase, the archaeal presenilin homolog PSH faithfully processes the substrate APP C99 into A beta 42, A beta 40, and A beta 38. The molar ratio of the cleavage products A beta 42 over A beta 40 by PSH is nearly identical to that by gamma-secretase. The proteolytic activity of PSH is specifically suppressed by presenilin-specific inhibitors. Known modulators of gamma-secretase also modulate PSH similarly in terms of the A beta 42/A beta 40 ratio. Structural analysis reveals association of a known gamma-secretase inhibitor with PSH between its two catalytic aspartate residues. These findings identify PSH as a surrogate protease for the screening of agents that may regulate the protease activity and the cleavage preference of gamma-secretase.