Crystal Structure of Caspase-2, Apical Initiator of the Intrinsic Apoptotic Pathway

Schweizer, Andreas; Briand, Christophe; Grütter, Markus G.

doi:10.1074/jbc.m304895200

Cited by 96 publications

(104 citation statements)

References 45 publications

(68 reference statements)

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“…Nevertheless, although much remains to be deciphered about this caspase, recent work has demonstrated that caspase-2 plays critical and singular roles in the control of apoptosis induced by anti-Fas, cytokine deprivation, ␤-amyloid, etoposide, and other stress stimuli (36). Some studies show that initiator caspase-2 is involved in the early stage of apoptosis before mitochondrial dysfunction (11,13,14,36,37), whereas others show that caspase-2 acts downstream of mitochondria (34,38). The possible factors that regulate its activation are not fully understood.…”

Section: Resultsmentioning

confidence: 99%

Sequential Caspase-2 and Caspase-8 Activation Upstream of Mitochondria during Ceramideand Etoposide-induced Apoptosis

Lin¹,

Chen

Chang³

et al. 2004

Journal of Biological Chemistry

120

113

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Recently, caspase-2 was shown to act upstream of mitochondria in stress-induced apoptosis. Activation of caspase-8, a key event in death receptor-mediated apoptosis, also has been demonstrated in death receptor-independent apoptosis. The regulation of these initiator caspases, which trigger the mitochondrial apoptotic pathway, is unclear. Here we report a potential regulatory role of caspase-2 on caspase-8 during ceramide-induced apoptosis. Our results demonstrate the sequential events of initiator caspase-2 and caspase-8 activation, Bid cleavage and translocation, and mitochondrial damage followed by downstream caspase-9 and -3 activation and cell apoptosis after ceramide induction in T cell lines. The expression of truncated Bid (tBid) and the reduction in mitochondrial transmembrane potential were blocked by caspase-2 or caspase-8, but not caspase-3, knockdown using an RNA interference technique. Ceramide-induced caspase-8 activation, mitochondrial damage, and apoptosis were blocked in caspase-2 short interfering RNA-expressing cells. Therefore, caspase-2 acts upstream of caspase-8 during ceramide-induced mitochondrial apoptosis. Similarly, sequential caspase-2 and caspase-8 activation upstream of mitochondria was also observed in etoposide-induced apoptosis. These data suggest sequential initiator caspase-2 and caspase-8 activation in the mitochondrial apoptotic pathway induced by ceramide or etoposide.A mitochondrial apoptotic pathway is required for various death stimuli (1, 2). The involvement of initiator caspases before mitochondrial damage has been shown (3, 4). Caspase-8 activation followed by the cleavage of the Bcl-2 family protein Bid, a BH3 domain-containing proapoptotic protein, induces mitochondrial damage during death receptor-mediated apoptosis (5-8). Activation of caspase-8 also has been demonstrated in death receptor-independent apoptosis (9, 10). Caspase-2 recently was shown to act upstream of mitochondria to promote cytochrome c release and apoptosis (11)(12)(13)(14). The regulation of these initiator caspases leading to the mitochondria-mediated apoptotic pathway remains unresolved.Ceramide, a product of sphingolipid metabolism, regulates diverse cellular responses, including proliferation, differentiation, and apoptosis. Although the role of ceramide as a signaling molecule remains debatable (15, 16), some early work suggested that various extracellular agents and stress stimuli, such as tumor necrosis factor-␣ (TNF␣), Fas, chemotherapeutic agents, irradiation, and heat, might cause accumulation of ceramide. Ceramide modulates the biochemical and cellular processes that lead to apoptosis (17-21). The mechanisms by which ceramide regulates apoptotic events have not been fully defined. Ceramide activates a number of enzymes involved in stress-signaling pathways, including both protein kinases and protein phosphatases. A recent study indicates that ceramide-induced neuronal apoptosis is associated with dephosphorylation of Akt, Bcl2-associated death promoter (BAD), forkhead transcriptional ...

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Section: Resultsmentioning

confidence: 99%

Sequential Caspase-2 and Caspase-8 Activation Upstream of Mitochondria during Ceramideand Etoposide-induced Apoptosis

Lin¹,

Chen

Chang³

et al. 2004

Journal of Biological Chemistry

120

113

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“…Caspase-2 is exceptional in its requirement for an additional occupied S5 subsite for efficient substrate cleavage (Schweizer et al, 2003). In contrast to caspase-3 and -7, the presence of a small hydrophobic P5 residue conferred a 35-fold increase in catalytic efficiency, which may partly reflect a better burial of the P4 Asp residue.…”

Section: Basic Features and Classification Of Caspasesmentioning

confidence: 96%

“…The S4 subsite provides major specificity-conferring elements to different caspases (Degterev et al, 2003;Schweizer et al, 2003). Caspase-1 has the widest S4 subsite, which favors large hydrophobic residues.…”

Section: Basic Features and Classification Of Caspasesmentioning

confidence: 99%

Caspases in apoptosis and beyond

2008

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“…The active site cleft of caspase-2 bound to the peptapeptide inhibitor acetyl-Leu-Asp-Glu-Ser-Asp-aldehyde (Ac-LDESD-CHO), taken from PDB code 1PYO. 68 The caspase is shown as a translucent electrostatic potential surface where blue hues denote positive potential and red hues negative potential. (a) The deep basic cleft next to the catalytic Cys (yellow) and His (green) residues of the enzyme occupies the P 1 Asp residue and is conserved in all active caspase structures.…”

Section: What It Takes To Be a Caspasementioning

confidence: 99%

Caspase substrates

2006

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The relatively common occurrence of sequences within proteins that match the consensus substrate specificity of caspases in intracellular proteins suggests a multitude of substrates in vivo -somewhere in the order of several hundred in humans alone. Indeed, the list of proteins that are reported to be cleaved by caspases in vitro proliferates rapidly. However, only a few of these proteins have been rigorously established as biologically or pathologically relevant, bona fide substrates in vivo. Many of them probably simply represent 'innocent bystanders' or erroneous assignments. In this review we discuss concepts of caspase substrate recognition and specificity, give resources for the discovery and annotation of caspase substrates, and highlight some specific human or mouse proteins where there is strong evidence for biologic or pathologic relevance.

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Crystal Structure of Caspase-2, Apical Initiator of the Intrinsic Apoptotic Pathway

Cited by 96 publications

References 45 publications

Sequential Caspase-2 and Caspase-8 Activation Upstream of Mitochondria during Ceramideand Etoposide-induced Apoptosis

Sequential Caspase-2 and Caspase-8 Activation Upstream of Mitochondria during Ceramideand Etoposide-induced Apoptosis

Caspases in apoptosis and beyond

Caspase substrates

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