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O1–02–03: Change of cleavage precision by presenilin–dependent gamma–secretase
Author(s) -
Okochi Masayasu,
Tagami Shinji,
Takeda Masatoshi
Publication year - 2006
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.2006.05.255
Subject(s) - cleavage (geology) , proteolysis , presenilin , chemistry , mutant , intracellular , microbiology and biotechnology , cleavage factor , biochemistry , immunoprecipitation , biology , biophysics , gene , enzyme , alzheimer's disease , medicine , pathology , messenger rna , paleontology , disease , fracture (geology)
Background: An unusual characteristics of the PS-dependent intramembrane proteolysis is that some cleavage sites are not single but have a variety. Because of the variety, the cleavage precision can be defined. The cleavage precision is the ratio of the cleavage occurring in each site. The change of the cleavage precision plays a pathological role, since pathological ‘gain-of-function’ of many familial AD-associated PS or betaAPP mutants is considered to be the increase of Abeta42 production induced by change of gamma-cleavage precision. However, it is unclear whether any changes of the cleavage precision play a physiological role. Objective(s): Cleavage precision of betaAPP and Notch-1 were identified and characterized to reveal their pathological and physiological roles. Methods: Combined immunoprecipitation and semi-quantitive MALDI-TOF MS as well as separation of radiolabeled Abeta/Nbeta species and AICD/NICD species by electrophoresis was performed. The cells treated with or without the compounds were subjected to metabolic labeling with [35S] methionine for quantitative analysis. Results: The characteristics of cleavage precision determining process of Nbeta and Abeta are almost identical. Since many other type-1 membrane-bound receptors release intracellular domains by PS-dependent intramembrane proteolysis, we suspect that the release of Abetaor Nbeta-like peptides is a common feature of the proteolysis during RIP signaling. Moreover, the cleavage precision determining process of NICD and AICD are also similar. Conclusions: Our results propose physiological as well as pathological roles for precision of the intramembrane cleavage by PS/gamma-secretase.