Dilysine retrieval signal‐containing p24 proteins collaborate in inhibiting γ‐cleavage of amyloid precursor protein

摘要: J. Neurochem. (2010) 115, 771–781. Abstract γ-Secretase mediates intramembranous γ-cleavage and e-cleavage of β-amyloid precursor protein (APP) to liberate peptide (Aβ) APP intracellular domain respectively from the membrane. Although regulatory mechanism γ-secretase cleavage remains unresolved, a member p24 cargo family, named p24δ1 or TMP21, has been identified as an activity-modulating component. The family proteins are divided into four subfamilies (p24α, β, δ γ). In contrast p24δ1, p24β1 reportedly no effect on γ-cleavage. this study, we determined whether p24α2, p24γ3 p24γ4 modulates processing. Knockdown cellular p24α2 induced significant increase in Aβ generation but not production cell-based cell-free assays, whereas over-expression suppressed secretion. By contrast, secretion was altered by knockdown. Endogenous co-immunoprecipitated with core components complex, anti-p24α2 immunoprecipitate exhibited activity. Mutational disruption conserved dilysine ER-retrieval motifs perturbed inhibition Simultaneous knockdown, co-over-expression, these had additive synergistic generation. Our findings suggest that signal-containing proteins, bind complexes collaborate attenuating APP.