Phosphorylation of presenilin-2 regulates its cleavage by caspases and retards progression of apoptosis.
Mutations within the Presenilin-2 (PS-2) gene are associated with early onset familial Alzheimer's disease. The gene encodes a polytopic transmembrane protein that undergoes endoproteolytic processing resulting in the generation of N-terminal and C-terminal fragments (CTFs). PS-2 is also cleaved by proteases of the caspase family during apoptotic cell death. CTFs of PS-2 were shown to inhibit apoptosis, suggesting an important role in the regulation of programmed cell death. Recently, we found that the CTF of PS-2 is phosphorylated in vivo. We mapped the in vivo phosphorylation sites of PS-2 to serine residues 327 and 330, which are localized immediately adjacent to the cleavage sites of caspases after aspartate residues 326 and 329. Phosphorylation of PS-2 inhibits its cleavage by caspase-3. This effect can be mimicked by substitutions of serines 327 and 330 by aspartate or glutamate. In addition, the uncleavable form of PS-2 CTF was found to enhance its antiapoptotic properties, leading to a slower progression of apoptosis. These results demonstrate that PS-2 cleavage as well as its function in apoptosis can be regulated by protein phosphorylation. Alterations in the phosphorylation of PS-2 may therefore promote the pathogenesis of AD by affecting the susceptibility of neurons to apoptotic stimuli.
Walter
J
J
Central Institute of Mental Health, Department of Molecular Biology, J5, 68159 Mannheim, Germany.
Schindzielorz
A
A
Grünberg
J
J
Haass
C
C
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019556:COS Cells; D020169:Caspases / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D053766:Presenilin-2; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity; D014162:Transfection