Mechanism of cytotoxicity mediated by the C31 fragment of the amyloid precursor protein.
The cytoplasmic tail of the amyloid precursor protein (APP) contains two putatively cytotoxic peptides, Jcasp and C31, derived by caspase cleavage of APP. Jcasp is a fragment starting from the epsilon-secretase site to position 664, while C31 is a fragment from position 665 to the C-terminus. Our studies now showed that compared to C31, Jcasp appeared to play a minor role in cytotoxicity. In particular, inhibition of Jcasp generation by treatment of gamma-secretase inhibitor did not lead to any attenuation of C31-induced toxicity. Secondly, because C31 toxicity is largely absent in cells lacking endogenous APP, we determined, using a split beta-galactosidase complementary assay to monitor protein-protein interactions, the presence of APP associated complexes. Our results demonstrated that both APP homomeric and C31/APP heteromeric complexes were correlated with cell death, indicating that C31 complexes with APP to recruit the interacting partners that initiate the signals related to cellular toxicity.
Park
Sun Ah
SA
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Shaked
Gideon M
GM
Bredesen
Dale E
DE
Koo
Edward H
EH
D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D001224:Aspartic Acid / Q000235:genetics; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000096:biosynthesis* / Q000235:genetics; D004151:Dipeptides / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000235:genetics; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D051381:Rats
D016564:Amyloid beta-Protein Precursor; D003603:Cytotoxins; D004151:Dipeptides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D010446:Peptide Fragments; D001224:Aspartic Acid; D053829:Amyloid Precursor Protein Secretases
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