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P2‐316: I2PP2A regulates PP2A and GSK‐3beta activity and its role in Alzheimer's disease
Author(s) -
Wang JianZhi
Publication year - 2011
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2011.05.1194
Subject(s) - protein phosphatase 2 , gsk 3 , chemistry , hyperphosphorylation , microbiology and biotechnology , glycogen synthase , tau protein , phosphorylation , phosphatase , western blot , alzheimer's disease , biology , biochemistry , medicine , disease , gene
heimer’s disease since it participates in the generation of the toxic amyloid ß-peptide (Aß) from the amyloid precursor protein (APP). g-Secretase is a membrane bound protein complex consisting of four components; presenilin (PS), nicastrin, Aph-1, and Pen-2.While the catalytic core of the g-secretase complex is strongly associated with PS, less is known about the other components. The function of nicastrin has been debated during the last years. Despite several studies of the nicastrin protein, it is still unclear whether it is involved in substrate selectivity or has a more general role in the stabilization and maturation of the g-secretase complex. An artificial double mutant in PS1, F411Y/S438P, has previously been reported to be independent of nicastrin for g-secretase activity. Here, we focus on exploring the mechanism behind this in order to better understand the role of nicastrin for the g-secretase complex’s assembly and activity. Methods: We are using co-immunoprecipitation and affinity capturing methods as well as a luciferase reporter gene assay to analyze the composition of the g-secretase complex and its activity on APP and Notch processing. All experiments are based on nicastrin deficient cells. We have also investigated the insertion efficiency of the transmembrane domains with and without the PS1 double mutant by using an assay based on N-linked glycosylation. Results: We can confirm that the PS1 double mutant F411Y/S438P is able to process both APP and Notch without nicastrin but with reduced activity. Moreover, we have found that the membrane integration is not changed compared to wild type PS1 and results regarding the changed conformation of the catalytic site will be presented. Conclusions: By understanding how the PS1 double mutant F411Y/S438P can form active gsecretase complexes in the absence of nicastrin, we will get more insight into nicastrin’s function within the complex.