. The presenilin-2 loop peptide perturbs intracellular Ca2+ homeostasis and accelerates apoptosis. J Biol Chem. 2006 Jun 16;281(24):16649-55. PubMed.

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  1. Do presenilin enhancer 2 (PEN-2) and presenilin 2 (PS2) cytosolic loops have something in common? In this paper, Cai et al. report the initiation and acceleration of cellular apoptosis by a 22-mer peptide that is usually generated by presenilinase and caspase-3 cleavage of the PS2 loop. In zebra fish, we have found that the loop of another γ-secretase component, PEN-2, can protect embryos from undergoing apoptosis (Zetterberg et al., 2006). The cytosolic loop of the γ-secretase PEN-2 protects zebra fish embryos from apoptosis. Interestingly, Cai et al. found that the 22-mer interacts with inositol 1,4,5-trisphosphate receptor (InsP3R) and activates Ca2+ release from the endoplasmic reticulum. The finding raises some questions: In cultured cells, does InsP3R interact with PS2 C-terminal fragment prior to caspase-3 cleavage? Upon apoptotic stimulation, does InsP3R interact with 22-mer peptide generated by caspase-3 cleavage? The authors have generated an antibody against the PS2 loop region (anti-PS2LP), which could be used to detect coimmunoprecipitates with InsP3R.

    Because PS2 and PEN-2 are able to form a part of γ-secretase complex, it is anticipated that there is functional interaction between two loop regions of PS2 and PEN-2. Given that the PEN-2 loop region prevents apoptosis, is there a physical interaction between the PEN-2 loop and the PS2 22-mer? Does this 22-mer interfere with the γ-secretase activity? The physiological significance of PS2-InsP3R interaction should help us understand molecular pathways leading towards apoptosis. Because the γ-secretase has many substrates, it seems to be difficult to explore the possibility that PS2- or PEN-2-mediated apoptosis is independent of γ-secretase activity.

    References:

    . The cytosolic loop of the gamma-secretase component presenilin enhancer 2 protects zebrafish embryos from apoptosis. J Biol Chem. 2006 Apr 28;281(17):11933-9. PubMed.