The C-terminal Tail of Presenilin Regulates Omi/HtrA2 Protease Activity
Journal of Biological Chemistry
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
... . 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).