Substrate cleavage by caspases generates protein fragments with Smac/Diablo-like activities.
Smac/Diablo and HtrA2/Omi promote apoptosis by binding to and antagonizing IAP proteins, including the 'X chromosome-linked inhibitor of apoptosis' (XIAP). Here we show that caspase-mediated proteolysis of a limited subset of cell death substrates exposes functional Smac/Diablo-like N-termini after cleavage, which are able to bind to and antagonize XIAP. We propose that this mechanism may establish a feedforward sensitization of the apoptotic pathway and contribute to the functional redundancy of IAP antagonism. In addition, this may be particularly relevant in Alzheimer's disease since the caspase-generated C31 peptide, an established cytotoxin, acquires Smac/Diablo-like properties after apoptotic processing.
Merck Research Laboratories, Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Quebec, Canada H9R 4P8.
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Hell
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Saleh
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Crescenzo
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O'Connor-McCourt
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Nicholson
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D025461:Feedback, Physiological / Q000502:physiology; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000502:physiology; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000502:physiology; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051636:X-Linked Inhibitor of Apoptosis Protein
D016564:Amyloid beta-Protein Precursor; D051017:Apoptosis Regulatory Proteins; C066649:C31 protein, mouse; D002352:Carrier Proteins; C412403:DIABLO protein, human; D004791:Enzyme Inhibitors; D015395:Histocompatibility Antigens Class I; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D010446:Peptide Fragments; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D045304:Cytochromes c; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases