APH-1 interacts with mature and immature forms of presenilins and nicastrin and may play a role in maturation of presenilin-nicastrin complexes
APH-1 interacts with mature and immature forms of presenilins and nicastrin and may play a role in maturation of presenilin-nicastrin complexes
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DOI：
10.1074/jbc.m209499200
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发表时间：
2003-02-28
影响因子：
4.8
通讯作者：
St George-Hyslop, P
中科院分区：
文献类型：
--
作者：
Gu, YJ;Chen, FS;St George-Hyslop, P
APH-1和PEN-2基因调节线虫nicastrin和早老素的功能。在转染的哺乳动物细胞过表达标记APH-1蛋白的初步研究表明，这种遗传相互作用是由直接的物理相互作用介导的。使用人类1号染色体上编码的APH-1蛋白（APH-1（1）L;也称为APH-1a）作为原型，我们在这里报告，内源性形式的APH-1主要在细胞内膜区室中表达，包括内质网和顺式高尔基体。APH-1蛋白直接与高分子量复合物内的未成熟和成熟形式的早老素和nicastrin相互作用，所述复合物显示γ-分泌酶活性并且是γ-分泌酶活性的要素。事实上，APH-1蛋白可以结合nicastrin Delta 312 -369功能丧失突变体，其不经历糖基化成熟并且不运输超过内质网。内源性APH-1（1）L的表达水平可被APH-1家族的任何其他成员的过表达所抑制，表明它们的丰度是协同调节的。最后，虽然APH-1的缺乏使早老素不稳定，但与nicastrin和PEN-2相反，APH-1本身在缺乏早老素I或早老素2的功能性表达的细胞中仅适度地不稳定。综上所述，我们的数据表明，APH-1蛋白，特别是APH-1（1），可能在早老素-nicastrin复合物的初始组装和成熟中起作用。
APH-1 and PEN-2 genes modulate the function of nicastrin and the presenilins in Caenorhabditis elegans. Preliminary studies in transfected mammalian cells overexpressing tagged APH-1 proteins suggest that this genetic interaction is mediated by a direct physical interaction. Using the APH-1 protein encoded on human chromosome 1 (APH-1(1)L; also known as APH-1a) as an archetype, we report here that endogenous forms of APH-1 are predominantly expressed in intracellular membrane compartments, including the endoplasmic reticulum and cis-Golgi. APH-1 proteins directly interact with immature and mature forms of the presenilins and nicastrin within high molecular weight complexes that display gamma- and is an element of-secretase activity. Indeed APH-1 proteins can bind to the nicastrin Delta312-369 loss of function mutant, which does not undergo glycosylation maturation and is not trafficking beyond the endoplasmic reticulum. The levels of expression of endogenous APH-1(1)L can be suppressed by overexpression of any other members of the APH-1 family, suggesting that their abundance is coordinately regulated. Finally, although the absence of APH-1 destabilizes the presenilins, in contrast to nicastrin and PEN-2, APH-1 itself is only modestly destabilized in cells lacking functional expression of presenilin I or presenilin 2. Taken together, our data suggest that APH-1 proteins, and APH-1(1) in particular, may have a role in the initial assembly and maturation of presenilin-nicastrin complexes.