Caspase-8 is an initiator caspase, as are caspase-2 (EC?3.4.22.55), caspase-9 (EC?3.4.22.62) and caspase-10 (EC?3.4.22.63) [1]. Caspase-8 is the apical activator of the extrinsic (death receptor) apoptosis pathway, triggered by death receptor ligation [2]. It contains two tandem death effector domains (DEDs) in its N-terminal prodomain, which play a role in procaspase activation [1]. This enzyme is linked to cell surface death receptors such as Fas [1,5]. When Fas is aggregated by the Fas ligand, procaspase-8 is recruited to the death receptor where it is activated [1]. The enzyme has a preference for Glu at P3 and prefers small residues, such as Gly, Ser and Ala at the P1′ position. It has very broad P4 specificity, tolerating substrates with Asp, Val or Leu in this position [2,3,4]. Endogenous substrates for caspase-8 include procaspase-3, the pro-apoptotic Bcl-2 family member Bid, RIP, PAK2 and the caspase-8 activity modulator FLIPL?[4,5]. Belongs in peptidase family?C14.
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Strict requirement for Asp at position P1 and has a preferred cleavage sequence of (Leu/Asp/Val)-Glu-Thr-Asp-|-(Gly/Ser/Ala).
