The role of CAP3 in CD95 signaling: new insights into the mechanism of procaspase-8 activation.
Formation of the CD95 (APO-1/Fas) death inducing signaling complex (DISC) plays a central role in CD95 signaling. Previously, CD95 DISC composition was analyzed by two-dimensional gel electrophoresis and four major cytotoxicity-associated proteins (CAP1-4) were found. CAP1 and CAP2 were defined to be unmodified and phosphorylated FADD, respectively. CAP4 was identified as procaspase-8a. CAP3, however, has remained elusive. In this study, we demonstrate that CAP3 is an intermediate of procaspase-8 processing. CAP3 is generated within seconds of DISC formation and subsequently processed to the prodomain of procaspase-8a that is known as p26 (CAP5). These findings lead to new insights into the mechanism of procaspase-8 processing and apoptosis initiation.
Golks
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A
Division of Immunogenetics, Tumorimmunology Program, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Brenner
D
D
Schmitz
I
I
Watzl
C
C
Krueger
A
A
Krammer
P H
PH
Lavrik
I N
IN
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis; D053181:Caspase 8; D061945:Caspase Inhibitors; D020169:Caspases / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053418:Death Domain Receptor Signaling Adaptor Proteins; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D017434:Protein Structure, Tertiary; D015843:Serpins / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D053418:Death Domain Receptor Signaling Adaptor Proteins; D004792:Enzyme Precursors; C102316:SERPINB9 protein, human; D015843:Serpins; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019014:fas Receptor; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases