The C-terminal Tail of Presenilin Regulates Omi/HtrA2 Protease Activity

• Published in: The Journal of biological chemistry Vol. 279; no. 44; pp. 45844 - 45854
• Main Authors: Gupta, Sanjeev, Singh, Rajesh, Datta, Pinaki, Zhang, Zhijia, Orr, Christopher, Lu, Zhixian, Dubois, Garrett, Zervos, Antonis S, Meisler, Miriam H, Srinivasula, Srinivasa M, Fernandes-Alnemri, Teresa, Alnemri, Emad S
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 29.10.2004
• Subjects: Amino Acid Sequence; Apoptosis; Bacterial Proteins - metabolism; Enzyme Activation; HeLa Cells; High-Temperature Requirement A Serine Peptidase 2; Humans; Membrane Proteins - chemistry; Membrane Proteins - physiology; Mitochondrial Proteins; Molecular Sequence Data; Presenilin-1; Presenilin-2; Serine Endopeptidases - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M404940200

Presenilin mutations are responsible for most cases of autosomal dominant inherited forms of early onset Alzheimer disease. Presenilins play an important role in amyloid β-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 domain. 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 β-casein and induces cell death in an Omi/HtrA2-dependent manner. Consistent with these results, ectopic expression of full-length 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.