Interaction Between CHIP And PS1

Alzheimer's disease(AD) is characterized byβ-amyloid plaques consisting ofβ-amyloid(Aβ) peptides and neurofibrillary tangles consisting of hyperphosphorylated tau protein.Currently the most widely accepted view about the pathogenesis of AD is the Aβcascade hypothesis,which suggests that Aβaccumulation or an increased ratio of Aβ42 over Aβ40 play an important role in AD pathogenesis.Aβis proteolytically derived from its precursor protein APP through sequential cleavages by theβ-secretase and theγ-secretase complex comprising presenilins(PS),nicastrin,APH-1,and PEN-2.In addition to its involvement in theγ-secretase activity,PS1 participates in many other biological functions such as protein trafficking,calcium homeostasis,apoptosis,and tumorigenesis.We have previously identified a potential PS1-interacting protein,CHIP(carboxyl terminus of Hsc70 interacting protein),by yeast two-hybrid system using the PS1 265-467 amino acids as the bait.CHIP has been known to have two main functions: one is to help protein folding as a cofactor of heat shock proteins,the other is to degrade misfolding proteins as an E3 ligase.But the interaction between CHIP on PS1 and its physiological relevance have not been reported.In the present study,we confirmed the interaction between CHIP and PS1 by coimmunoprecipitation in mammalian cells.Immunoflurocence study also showed that CHIP and PS1 colocalize around the nucleus.To further identify the specific domain of CHIP that interacts with PS1,we constructed vectors containing different domains of CHIP.By coimmunoprecipitation we found that CHIP interacts with PS1 through it's TPR domain.Futhermore,our study shows that PS1 can stablize the CHIP-Hsp70 complex.Our results suggest a potential role of PS1 in modulating the heat shock protein system through its interaction with CHIP.