Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.36 (caspase-1)
 6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sf-caspase-1 is the most studied effector caspase of Lepidoptera. Its activation is believed to follow a two-step mechanism: The first step requires cleavage by an initiator caspase at D195 (between the large and small subunits) releasing the C-terminal small subunit. This is blocked by the baculovirus caspase inhibitor P49. The second step removes the N-terminal prodomain by cleavage at D28 to generate the large subunit that is blocked by the baculovirus caspase inhibitor P35. In this study, we identified an alternative mechanism of Sf-caspase-1 activation. This additional two-step mechanism involves first cleavage of pro-Sf-caspase-1 at D28 to remove the N-terminal prodomain and subsequently cleavage at D195 to generate the large and small subunits. Both mechanisms are triggered by apoptotic stimuli following a distinct pattern. We also showed that expression of Sf-caspase-1 was upregulated upon reception of apoptotic stimuli. Different from all published data, this upregulation occurred as a post-transcriptional event. Moreover, we proved that the stronger the stimuli, the higher the upregulation. And we demonstrated that P49 and P35 inhibited the cleavage at D28 and D195 respectively, independently of wether the first cleavage was at D195 or at D28.
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PMID:Activation pathways and signal-mediated upregulation of the insect Spodoptera frugiperda caspase-1. 1653 78

Baculovirus proteins P49 and P35 are potent suppressors of apoptosis in diverse organisms. Although related, P49 and P35 inhibit initiator and effector caspases, respectively, during infection of permissive insect cells. The molecular basis of this novel caspase specificity is unknown. To advance strategies for selective inhibition of the cell death caspases, we investigated biochemical differences between these baculovirus substrate inhibitors. We report here that P49 and P35 use similar mechanisms for stoichiometric inhibition that require caspase cleavage of their reactive site loops (RSL) and chemical contributions of a conserved N-terminal cysteine to stabilize the resulting inhibitory complex. Our data indicated that P49 functions as a homodimer that simultaneously binds two caspases. In contrast, P35 is a monomeric, monovalent inhibitor. P49 and P35 also differ in their RSL caspase recognition sequences. We tested the role of the P(4)-P(1) recognition motif for caspase specificity by monitoring virus-induced proteolytic processing of Sf-caspase-1, the principal effector caspase of the host insect Spodoptera frugiperda. When P49's TVTD recognition motif was replaced with P35's DQMD motif, P49 was impaired for inhibition of the initiator caspase that cleaves and activates pro-Sf-caspase-1 and instead formed a stable inhibitory complex with active Sf-caspase-1. In contrast, the effector caspase specificity of P35 was unaltered when P35's DQMD motif was replaced with TVTD. We concluded that the TVTD recognition motif is required but not sufficient for initiator caspase inhibition by P49. Our findings demonstrate a critical role for the P(4)-P(1) recognition site in caspase specificity by P49 and P35 and indicate that additional determinants are involved in target selection.
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PMID:Reactive-site cleavage residues confer target specificity to baculovirus P49, a dimeric member of the P35 family of caspase inhibitors. 1850 88