Different cofactor activities in gamma-secretase assembly: evidence for a nicastrin-Aph-1 subcomplex |
| |
Authors: | Hu Yue Fortini Mark E |
| |
Institution: | University of Pennsylvania School of Medicine, Philadelphia 19104, USA. |
| |
Abstract: | The gamma-secretase complex is required for intramembrane cleavage of several integral membrane proteins, including the Notch receptor, where it generates an active signaling fragment. Four putative gamma-secretase components have been identified-presenilin (Psn), nicastrin (Nct), Aph-1, and Pen-2. Here, we use a stepwise coexpression approach to investigate the role of each new component in gamma-secretase assembly and activation. Coexpression of all four proteins leads to high level accumulation of mature Psn and increased proteolysis of Notch. Aph-1 and Nct may form a subcomplex that stabilizes the Psn holoprotein at an early step in gamma-secretase assembly. Subcomplex levels of Aph-1 are down-regulated by stepwise addition of Psn, suggesting that Aph-1 might not enter the mature complex. In contrast, Pen-2 accumulates proportionally with Psn, and is associated with Psn endoproteolysis during gamma-secretase assembly. These results demonstrate that Aph-1 and Pen-2 are essential cofactors for Psn, but that they play different roles in gamma-secretase assembly and activation. |
| |
Keywords: | presenilin Pen-2 Notch Drosophila amyloid |
本文献已被 PubMed 等数据库收录! |
|