Specific domains in anterior pharynx-defective 1 determine its intramembrane interactions with nicastrin and presenilin.
Specific domains in anterior pharynx-defective 1 determine its intramembrane interactions with nicastrin and presenilin.
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DOI：
10.1016/j.neurobiolaging.2009.12.028
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发表时间：
2012-02
影响因子：
4.2
通讯作者：
Wong, Philip C.
中科院分区：
文献类型：
--
作者：
Chiang, Po-Min;Fortna, Ryan R.;Price, Donald L.;Li, Tong;Wong, Philip C.
γ-分泌酶是一种多亚基跨膜蛋白酶，由早老素、nicastrin、早老素增强子2和前咽缺陷1组成，参与I型膜蛋白（包括淀粉样前体蛋白（APP））的调节性膜内蛋白水解。虽然Aph-1被认为在γ-分泌酶复合物的组装中起结构作用，并且Aph-1的几个跨膜结构域（TMD）已被证明对其功能至关重要，但Aph-1的其他结构域的重要性仍然是难以捉摸的。我们筛选了一系列Aph-1突变体，并重点关注分布在人APH-1aS的6个不同TMD中的9个突变，评估它们补充缺乏Aph-1的小鼠胚胎成纤维细胞的能力。我们发现Aph-1a的TMD 4（G126）和TMD 5（H171）突变阻止了Nct/Aph-1亚复合物的形成。重要的是，尽管APH-1aS的TMD 3（Q83/E84/R85）和TMD 6（H197）突变不影响Nct/Aph-1亚复合物的形成，但这两种突变都阻止了PS1的进一步缔合/内蛋白水解。我们提出了一个模型，确定关键的TMDs的Aph-1的协会与Nct和PS的γ-分泌酶组件的逐步组装。
γ-Secretase, a multi-subunit transmembrane protease comprised of presenilin, nicastrin, presenilin enhancer 2, and anterior pharynx-defective 1, participates in the regulated intramembrane proteolysis of Type I membrane proteins including the amyloid precursor protein (APP). Although Aph-1 is thought to play a structural role in the assembly of γ-secretase complex and several transmembrane domains (TMDs) of Aph-1 have been shown to be critical for its function, the importance of the other domains of Aph-1 remains elusive. We screened a series of Aph-1 mutants and focused on 9 mutations distributed in 6 different TMDs of human APH-1aS, assessing their ability to complement mouse embryonic fibroblasts lacking Aph-1. We showed that mutations in TMD4 (G126) and TMD5 (H171) of Aph-1a prevented the formation of the Nct/Aph-1 subcomplex. Importantly, although mutations in TMD3 (Q83/E84/R85) and TMD6 (H197) of APH-1aS did not affect Nct/Aph-1 subcomplex formation, both mutations prevented further association/endoproteolysis of PS1. We propose a model that identifies critical TMDs of Aph-1 for associations with Nct and PS for the stepwise assembly of γ-secretase components.
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