Presenilin mutations are responsible for most cases of autosomal dominant inherited forms of early onset Alzheimer disease. Presenilins play an important role in amyloid ␤-precursor processing, NOTCH receptor signaling, and apoptosis. However, the molecular mechanisms by which presenilins regulate apoptosis are not fully understood. Here, we report that presenilin-1 (PS1) regulates the proteolytic activity of the serine protease Omi/HtrA2 through direct interaction with its regulatory PDZ

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... . We show that a peptide corresponding to the cytoplasmic C-terminal tail of PS1 dramatically increases the proteolytic activity of Omi/HtrA2 toward the inhibitor of apoptosis proteins and ␤-casein and induces cell death in an Omi/HtrA2-dependent manner. Consistent with these results, ectopic expression of fulllength PS1, but not PS1 lacking the C-terminal PDZ binding motif, potentiated Omi/HtrA2-induced cell death. Our results suggest that the C terminus of PS1 is an activation peptide ligand for the PDZ domain of Omi/ HtrA2 and may regulate the protease activity of Omi/ HtrA2 after its release from the mitochondria during apoptosis. This mechanism of Omi/HtrA2 activation is similar to the mechanism of activation of the related bacterial DegS protease by the outer-membrane porins. The presenilin proteins, presenilin-1 (PS1) 1 and presenilin-2 (PS2), have been implicated in the etiology of Alzheimer disease (AD) in humans (1-3). Mutations in the PS1 gene are responsible for about 60% of familial early-onset AD cases (4).