Death caspase-1
Protein and peptide inhibitors and activators of caspases Inhibitors of apoptosis (IAPs) are a family of proteins that bear baculoviral IAP repeats (BIRs) and regulate apoptosis
in vertebrates and Drosophila. The yeasts Saccharomyces cerevisiae and Schizosaccharomyces
pombe both encode a single IAP, designated BIR1 and bir1, respectively, each of which bears two BIR (baculovirus IAP repeat) motifs. In rich
medium, BIR1 mutant S. cerevisiae undergo normal vegetative growth and mitosis. Under starvation conditions,
however, BIR1 mutant diploids form spores inefficiently, instead undergoing pseudohyphal differentiation. Most
spores that do form fail to survive beyond two divisions after germination. bir1 mutant S. pombe spores also die in the early divisions after spore
germination and become blocked at the metaphase/anaphase transition. These mutants are unable to elongate their mitotic spindle. Rather than inhibiting
caspase-mediated cell death, yeast IAP proteins have roles in cell division and appear to act in a way similar to the IAPs from Caenorhabditis elegans and
the mammalian IAP Survivin (Uren, 1999).
Other IAPs bearing BIRs that resemble those from the yeasts may also have roles in spindle function. Of the vertebrate IAP genes, the sequence and exon
structure of the yeast IAPs is most closely related to that of the mammalian IAP Survivin. survivin expression increases during the G2/M phase of cell cycle,
and Survivin localizes to the mitotic spindle in vivo and cosediments with polymerized tubulin. RNA-mediated gene interference of one of the IAPs
from C. elegans causes abnormalities in cytokinesis during embryonal cell divisions (Uren, 1999 and references therein).
Although it is not clear whether vertebrate and insect IAPs function primarily by blocking caspase activation signals or by binding directly to
caspases, most are thought to inhibit a caspase-dependent apoptotic mechanism. Survivin has been reported to bind directly to, and inhibit,
caspases 3 and 7, but its homologs in C. elegans, bir-1 and bir-2, appear to have no role in the control of cell death, and the phenotype caused by
inactivation of one of the C. elegans IAPs can be suppressed partially by transgenic expression of survivin. Because neither S. pombe nor
S. cerevisiae appears to encode caspases, and neither has been shown to use a cell suicide program, Bir1 and BIR1 are unlikely to function by inhibiting
cell death mechanisms resembling those in metazoans.
The structural and functional similarities between human Survivin, cerevisiae BIR1, pombe Bir1, and the BIR-bearing proteins from C. elegans suggest that
they share conserved roles in cell division (Uren, 1999 and references therein).
The mitochondrial protein
Smac/DIABLO performs a critical function in apoptosis by eliminating the
inhibitory effect of IAPs (inhibitor of apoptosis proteins) on caspases. Smac/DIABLO promotes not only the proteolytic activation of
procaspase-3 but also the enzymatic activity of mature caspase-3, both of which
depend upon its ability to interact physically with IAPs. The crystal structure
of Smac/DIABLO at 2.2 Å resolution reveals that it homodimerizes through an
extensive hydrophobic interface. Missense mutations inactivating this dimeric
interface significantly compromise the function of Smac/DIABLO. As in the
Drosophila proteins Reaper, Grim and Hid, the amino-terminal amino acids of
Smac/DIABLO are indispensable for its function, and a seven-residue peptide
derived from the amino terminus promotes procaspase-3 activation in vitro. These
results establish an evolutionarily conserved structural and biochemical basis
for the activation of apoptosis by Smac/DIABLO (Chai, 2000).
Apoptosis is an essential process in the development and homeostasis of all
metazoans. The inhibitor-of-apoptosis (IAP) proteins suppress cell death by
inhibiting the activity of caspases; this inhibition is performed by the
zinc-binding BIR domains of the IAP proteins. The mitochondrial protein
Smac/DIABLO promotes apoptosis by eliminating the inhibitory effect of IAPs
through physical interactions. Amino-terminal sequences in Smac/DIABLO are
required for this function, because mutation of the very first amino acid leads to
loss of interaction with IAPs and the concomitant loss of Smac/DIABLO function. The high-resolution crystal structure of Smac/DIABLO complexed with
the third BIR domain (BIR3) of XIAP is reported in this study. These results show that the N-terminal four residues (Ala-Val-Pro-Ile) in Smac/DIABLO recognize a surface groove on BIR3, with the first residue Ala binding a hydrophobic pocket and making five hydrogen bonds to neighboring residues on BIR3. These observations provide a structural explanation for the roles of the Smac N terminus as well as the conserved N-terminal sequences in the Drosophila proteins Hid/Grim/Reaper. In conjunction with other observations, these results reveal how Smac may relieve IAP inhibition of caspase-9 activity. In addition to explaining a number of biological
observations, this structural analysis identifies potential targets for drug
screening (Wu, 2000).
MIHA is an inhibitor of apoptosis protein (IAP) that can inhibit cell death by
direct interaction with caspases, the effector proteases of apoptosis. DIABLO is
a mammalian protein that can bind to IAPs and antagonize their antiapoptotic
effect, a function analogous to that of the proapoptotic Drosophila molecules,
Grim, Reaper, and HID. After UV radiation, MIHA prevents
apoptosis by inhibiting caspase 9 and caspase 3 activation. Unlike Bcl-2, MIHA
functions after release of cytochrome c and DIABLO from the mitochondria and
is able to bind to both processed caspase 9 and processed caspase 3 to prevent
feedback activation of their zymogen forms. Once released into the cytosol,
DIABLO binds to MIHA and disrupts its association with processed caspase 9,
thereby allowing caspase 9 to activate caspase 3, resulting in apoptosis (Ekert, 2001).
The molecular mechanism(s) that regulate apoptosis by caspase inhibition remain poorly understood. The main endogenous inhibitors are members of the IAP family and are exemplified by XIAP, which regulates the initiator caspase-9, and the executioner caspases-3 and -7. The crystal structure is reported of the second BIR domain of
XIAP (BIR2) in complex with caspase-3, at a resolution of 2.7 Å, revealing the structural basis for inhibition.
The inhibitor makes limited contacts through its BIR domain to the surface of the enzyme, and most contacts to
caspase-3 originate from the N-terminal extension. This lies across the substrate binding cleft, but in reverse
orientation compared to substrate binding. The mechanism of inhibition is due to a steric blockade prohibitive of
substrate binding, and is distinct from the mechanism utilized by synthetic substrate analog inhibitors (Riedl, 2001).
X-linked inhibitor-of-apoptosis protein (XIAP) interacts with caspase-9 and
inhibits its activity, whereas Smac (also known as DIABLO) relieves this
inhibition through interaction with XIAP. XIAP associates with
the active caspase-9-Apaf-1 holoenzyme complex through binding to the amino
terminus of the linker peptide on the small subunit of caspase-9, which becomes
exposed after proteolytic processing of procaspase-9 at Asp315. Supporting this
observation, point mutations that abrogate the proteolytic processing but not
the catalytic activity of caspase-9, or deletion of the linker peptide,
prevents caspase-9 association with XIAP and its concomitant inhibition. The N-terminal four residues of caspase-9 linker peptide share
significant homology with the N-terminal tetra-peptide in mature Smac and in the
Drosophila proteins Hid/Grim/Reaper, defining a conserved class of IAP-binding
motifs. Consistent with this finding, binding of the caspase-9 linker peptide
and Smac to the BIR3 domain of XIAP is mutually exclusive, suggesting that Smac
potentiates caspase-9 activity by disrupting the interaction of the linker
peptide of caspase-9 with BIR3. These studies reveal a mechanism in which binding
to the BIR3 domain by two conserved peptides, one from Smac and the other one
from caspase-9, has opposing effects on caspase activity and apoptosis (Srinivasula, 2001).
The mechanisms by which p35, a baculovirus inhibitor of cell death proteases, and members of the baculovirus inhibitor of apoptosis (IAP) family inhibit apoptosis appear to differ. An investigation was carried out of the ability of Sf-caspase-1 and two mammalian caspases (caspase-1 and caspase-3)
to induce apoptosis in Spodoptera frugiperda Sf-21 insect cells. While the transient expression of the
pro-Sf-caspase-1 does not induce apoptosis, expression of the pro-domain deleted form, p31, or
coexpression of the two subunits of mature Sf-caspase-1, p19 and p12, induce apoptosis in Sf-21 cells.
The behavior of Sf-caspase-1 resembles that of the closely related mammalian caspase, caspase-3, and
contrasts with that of the mammalian caspase-1, the pro-form of which is active in inducing
apoptosis in Sf-21 cells. The baculovirus caspase inhibitor P35 blocks apoptosis induced by active
forms of all three caspases. In contrast, members of the baculovirus inhibitor of apoptosis (IAP) family
fail to block active caspase-induced apoptosis. However, during viral infection, expression of OpIAP or
CpIAP blocks the activation of pro-Sf-caspase-1 and the associated induction of apoptosis. Thus, the
mechanism by which baculovirus IAPs inhibit apoptosis is distinct from the mechanism by which P35
blocks apoptosis and involves inhibition of the activation of pro-caspases like Sf-caspase-1 (Seshagiri, 1997).
The baculovirus protein p35 inhibits programmed cell death in such diverse animals as insects,
nematodes and mammals. p35 protein has been shown to be a substrate for and inhibitor of the
C. elegans cell-death protease CED-3 and a substrate for four CED-3-like
vertebrate cysteine protease activities implicated in apoptosis in mammals. A p35 mutation that greatly
reduces p35 activity in vitro as a CED-3 substrate and inhibitor abolishes p35 activity in vivo in
protecting against cell death in C. elegans. Introduction of the CED-3 cleavage site in p35 into the
cowpox virus protein crmA, which inhibits mammalian apoptosis but not programmed cell death in C.
elegans, causes crmA to block CED-3-mediated cell death. These observations suggest that p35 may
prevent programmed cell death in C. elegans and other species by acting as a competitive inhibitor of
cysteine proteases (Xue, 1995).
The baculovirus p35 gene product inhibits virally induced apoptosis, developmental cell death in
C. elegans and Drosophila, and neuronal cell death in mammalian systems. Therefore, p35
likely inhibits a component of the death machinery that is both ubiquitous and highly conserved in
evolution. p35 also inhibits Fas- and tumor necrosis factor
(TNF)-induced apoptosis. Additionally, p35 blocks TNF- and Fas-induced proteolytic cleavage of the
death substrate poly(ADP-ribose) polymerase from its native 116-kDa form to the characteristic
85-kDa form. This cleavage is thought to be catalyzed by an aspartate-specific protease of the
interleukin 1 beta-converting enzyme family designated prICE. These data suggest
that p35 must directly or indirectly inhibit prICE. Given that p35 inhibits both TNF and Fas killing, along
with previous reports of its ability to block developmental, viral, and x-irradiation-induced cell death, the
present results indicate that TNF- and Fas-mediated apoptotic pathways must have components in
common with these highly conserved death programs (Biedler, 1995).
The baculovirus p35-encoding gene (p35) is an
inhibitor of virus-induced apoptosis in insect cells. Expression of p35 in C.
elegans prevents the death of cells normally programmed to die. This suppression of developmentally
programmed cell death results in the appearance of extra surviving cells. Expression of p35 can rescue the
embryonic lethality of a mutation in ced-9, an endogenous gene homologous to the mammalian
apoptotic suppressor bcl-2, whose absence leads to ectopic cell deaths. These results support the
hypothesis that viral infection can activate the same cell death pathway as is used during normal
development and suggest that baculovirus p35 may act downstream or independently of ced-9 in this
pathway (Sugimoto, 1994).
Members of the inhibitor of apoptosis (IAP) family of proteins are highly conserved through
evolution. However, the mechanisms by which these proteins interfere with apoptotic
cell death have been enigmatic. One of the human IAP
family proteins, XIAP, can bind to and potently inhibit specific cell death proteases
(caspases) that function in the distal portions of the proteolytic cascades involved in
apoptosis. Three of the other known members of the
human IAP family (c-IAP-1, c-IAP-2 and NAIP) have also been investigated. Similar to XIAP, in vitro binding
experiments indicate that c-IAP-1 and c-IAP-2 bind specifically to the terminal
effector cell death proteases, caspases-3 and -7, but not to the proximal protease
caspase-8, caspases-1 or -6. In contrast, NAIP fails to bind tightly to any of these
proteases. Recombinant c-IAP-1 and c-IAP-2 also inhibits the activity of caspases-3
and -7 in vitro, whereas NAIP does not. The BIR
domain-containing region of c-IAP-1 and c-IAP-2 is sufficient for inhibition of these
caspases, though proteins that retained the RING domain are somewhat more
potent. Utilizing a cell-free system in which caspases are activated in cytosolic
extracts by addition of cytochrome c, c-IAP-1 and c-IAP-2 inhibit both the
generation of caspase activities and proteolytic processing of pro-caspase-3. Similar
results are obtained in intact cells when c-IAP-1 and c-IAP-2 are overexpressed
by gene transfection, and apoptosis is induced by the anticancer drug, etoposide.
Cleavage of c-IAP-1 or c-IAP-2 is not observed when interacting with the
caspases, implying a different mechanism from the baculovirus p35 protein, the broad
spectrum suicide inactivator of caspases. Taken together, these findings suggest that
c-IAP-1 and c-IAP-2 function in a manner similar to XIAP by inhibiting the distal cell death
proteases, caspases-3 and -7, whereas NAIP presumably inhibits apoptosis via other
targets (Roy, 1997).
The gene encoding human IAP-like protein (hILP) is one of several mammalian genes with sequence
homology to the baculovirus inhibitor-of-apoptosis protein (iap) genes. hILP can
block apoptosis induced by a variety of extracellular stimuli, including UV light, chemotoxic drugs, and
activation of the tumor necrosis factor and Fas receptors. hILP also protects against cell death
induced by members of the caspase family, the cysteine proteases that are thought to be the principal
effectors of apoptosis. hILP and Bcl-xL were compared for their ability to affect several steps in the
apoptotic pathway. Redistribution of cytochrome c from mitochondria, an early event in apoptosis, is
not blocked by overexpression of hILP but is inhibited by Bcl-xL. In contrast, hILP, but not Bcl-xL,
inhibits apoptosis induced by microinjection of cytochrome c. These data suggest that while Bcl-xL
may control mitochondrial integrity, hILP can function downstream of mitochondrial events to inhibit
apoptosis (Duckett, 1998).
The inhibitor-of-apoptosis (IAP) family of genes has an evolutionarily conserved role in regulating programmed cell death in animals ranging from insects to humans. Ectopic expression of human IAP proteins can suppress cell death induced by a variety of stimuli, but the mechanism of this inhibition had been previously unknown. Guman X-chromosome-linked IAP directly inhibits at least two members of the caspase family of cell-death proteases: caspase-3 and caspase-7. Since the caspases are highly conserved throughout the animal kingdom and are the principal effectors of apoptosis,
these findings suggest how IAPs might inhibit cell death, providing evidence for a mechanism of action for these mammalian cell-death suppressors (Devereaux, 1997).
Members of both the NF-kappaB/Rel and inhibitor of apoptosis (IAP) protein families have been implicated in signal transduction programs that prevent cell death elicited by the cytokine tumor necrosis factor alpha (TNF). Although NF-kappaB (Drosophila homolog: Dorsal) appears to stimulate the expression of specific protective genes, neither the identities of these genes nor the precise role of IAP proteins in this anti-apoptotic process are known. NF-kappaB is required for TNF-mediated induction of the gene encoding human c-IAP2. When overexpressed in mammalian cells, c-IAP2 activates NF-kappaB and suppresses TNF cytotoxicity. Both of these c-IAP2 activities are blocked in vivo by coexpressing a dominant form of IkappaB that is resistant to TNF-induced degradation. In contrast to wild-type c-IAP2, a mutant lacking the C-terminal RING domain inhibits NF-kappaB induction by TNF and enhances TNF killing. These findings suggest that c-IAP2 is critically involved in TNF signaling and exerts positive feedback control on NF-kappaB via an IkappaB targeting mechanism. Functional coupling of NF-kappaB and c-IAP2 during the TNF response may provide a signal amplification loop that promotes cell survival rather than death (Chu, 1997).
The oncoprotein v-Rel, a member of the Rel/NF-kappaB family of transcription factors, induces
neoplasias and inhibits apoptosis. To identify differentially regulated cellular genes and to evaluate their
relevance to transformation and apoptosis in v-Rel-transformed cells, mRNA differential display has
been used. One of the recovered cDNAs corresponds to a gene that is highly expressed in
v-Rel-transformed fibroblasts. Analysis of the isolated full-length cDNA of a chicken
inhibitor-of-apoptosis protein (ch-IAP1) reveals that it encodes a 68-kDa protein that is highly
homologous to members of the IAP family, such as human c-LAP1. Like other IAPs, ch-IAP1
contains the N-terminal baculovirus IAP repeats and C-terminal RING finger motifs. Northern blot
analysis identifies a 3.3-kb ch-IAP1 transcript expressed at relatively high levels in the spleen, thymus,
bursa, intestine, and lungs. Expression of v-Rel in fibroblasts, a B-cell line, and spleen cells up-regulates
the expression of ch-IAP1. In contrast, ch-IAP1 expression levels are low in chicken cell lines
transformed by several other unrelated tumor viruses. ch-IAP1 is expressed predominantly in the
cytoplasm of the v-Rel-transformed cells. ch-IAP1 suppresses mammalian cell apoptosis induced by
the overexpression of the interleukin-1-converting enzyme. Expression of exogenous ch-IAP1 in
temperature-sensitive v-Rel transformed spleen cells inhibits apoptosis of these cells at the
nonpermissive temperature. Collectively, these results suggest that ch-IAP1 is induced during the
v-Rel-mediated transformation process and functions as a suppressor of apoptosis in
v-Rel-transformed cells (You, 1997).
crmA is a cowpox virus gene that encodes a protease inhibitor of the serpin family. The only reported
target for the CrmA protein is the cysteine protease interleukin-1 beta converting enzyme (ICE). A function of crmA
may be to inhibit cell death, since a major mechanism of viral clearance is the immune
system-mediated induction of apoptosis in infected cells. The tumor necrosis factor receptor and the
Fas antigen are two cytokine receptors that can
eliminate virus-infected cells by engaging and activating the death pathway. Remarkably, crmA isfound to be an exceptionally potent inhibitor of
apoptosis induced by both these receptors, capable of blocking the cell death program even at
pharmacological doses of the death stimulus. Therefore, an important new function for crmA is the
inhibition of cytokine-induced apoptosis. Further, the data suggest that a protease, either ICE or a
related crmA-inhibitable protein, is a component of the Fas- and tumor necrosis factor-induced cell
death pathways (Tewari, 1995c).
Expression of poxvirus gene product crmA inhibits cytotoxicity induced by anti-Fas antibody or tumour
necrosis factor (TNF). A specific ICE inhibitor tetrapeptide
(acetyl-Tyr-Val-Ala-Asp-chloromethylketone) also prevents apoptosis induced by anti-Fas
antibody. These results suggest an involvement of an ICE-like protease in Fas-mediated apoptosis and
TNF-induced cytotoxicity (Enari, 1995).
CrmA, a poxvirus gene product with a serpin-like structure, blocks a variety of apoptotic death events
in cultured cells. Based on the ability of CrmA to inhibit the interleukin-1beta converting enzyme in
vitro, it has been speculated that interleukin-1beta converting enzyme-related proteases (caspases)
essential for apoptosis are the cellular targets of CrmA. Rabbitpox virus
CrmA/SPI-2 inhibits the cleavage of lamin A (See Drosophila Lamin) mediated by a caspase in a cell-free system of
apoptosis. In the presence of CrmA/SPI-2, nuclear apoptosis in vitro is blocked at an intermediate
stage after collapse of the chromatin against the nuclear periphery and before nuclear shrinkage and
disintegration into apoptotic body-like fragments. One of five caspases active in the extracts is inhibited both by CrmA/SPI-2 and by
a peptide spanning the lamin A apoptotic cleavage site. These results reveal that CrmA/SPI-2 can
inhibit a caspase responsible both for lamin A cleavage and for the nuclear disintegration characteristic
of apoptosis (Takahashi, 1996).
ARC [apoptosis repressor with caspase recruitment domain (CARD)] is a newly characterized protein that contains an N-terminal CARD fused to a C-terminal region rich in proline/glutamic acid residues. The
CARD domain of ARC exhibits significant homology to the prodomains of apical caspases and the CARDs present in the cell
death regulators Apaf-1 and RAIDD. Immunoprecipitation analysis reveals that ARC interacts with caspase-2, -8, and
Caenorhabditis elegans CED-3, but not with caspase-1, -3, or -9. ARC inhibits apoptosis induced by caspase-8 and CED-3
but not that mediated by caspase-9. Further analysis has shown that the enzymatic activity of caspase-8 is inhibited by ARC in
293T cells. Consistent with the inhibition of caspase-8, ARC attenuates apoptosis induced by FADD and TRADD and that
triggered by stimulation of death receptors coupled to caspase-8, including CD95/Fas, tumor necrosis factor-R1, and
TRAMP/DR3. Remarkably, the expression of human ARC is primarily restricted to skeletal muscle and cardiac tissue. Thus,
ARC represents an inhibitor of apoptosis expressed in muscle that appears to selectively target caspases. Delivery of ARC by
gene transfer or enhancement of its endogenous activity may provide a strategy for the treatment of diseases that are
characterized by inappropriately increased cell death in muscle tissue (Koseki, 1998).
The inhibitor of apoptosis (IAP) proteins suppress cell death by inhibiting the catalytic activity of caspases. The crystal structure of caspase-7 is presented in this study in complex with a potent inhibitory fragment from XIAP at 2.45 Å
resolution. An 18-residue XIAP peptide binds the catalytic groove of caspase-7, making extensive contacts to the residues that are essential for its catalytic activity. Strikingly, despite a reversal of relative orientation, a subset of interactions between caspase-7 and XIAP closely resemble those between caspase-7 and its tetrapeptide inhibitor DEVD-CHO. These biochemical and structural analyses reveal that the BIR domains are dispensable for the inhibition of caspase-3 and -7. This study provides a structural basis for the design of the next-generation caspase inhibitors (Chai, 2001).
The inhibitor of apoptosis proteins (IAPs) represent the only endogenous caspase inhibitors and are
characterized by the presence of baculoviral IAP repeats (BIRs). The crystal structure of the
complex between human caspase-7 and XIAP (BIR2 and the proceeding linker) are reported in this study. The structure surprisingly
reveals that the linker is the only contacting element for the caspase, while the BIR2 domain is invisible in the
crystal. The linker interacts with and blocks the substrate groove of the caspase in a backward fashion, distinct
from substrate recognition. Structural analyses suggest that the linker is the energetic and specificity determinant
of the interaction. Further biochemical characterizations clearly establish that the linker harbors the major
energetic determinant. The caspase inhibitory function of IAPs may be relieved by a newly identified
novel mitochondrial protein Smac/DIABLO. Smac is released into
the cytosol during apoptosis and decreases the cellular threshold for apoptotic stimuli. It appears to be a
functional homolog of the Drosophila proteins Reaper, Hid, and Grim, which are also IAP neutralizers. The biochemical basis of Smac function relies on a direct physical association with multiple IAPs while the BIR2 domain serves as a regulatory element for caspase binding and Smac neutralization (Huang, 2001).
The X-linked inhibitor of apoptosis protein (XIAP) uses its second baculovirus
IAP repeat domain (BIR2) to inhibit the apoptotic executioner caspase-3 and -7.
Structural studies have demonstrated that it is not the BIR2 domain itself but a
segment N-terminal to it that directly targets the activity of these caspases.
These studies failed to demonstrate a role of the BIR2 domain in inhibition. Site-directed
mutagenesis of BIR2 and its linker were used to determine the mechanism
of executioner caspase inhibition by XIAP. The BIR2 domain
contributes substantially to inhibition of executioner caspases. A surface
groove on BIR2, which also binds to Smac/DIABLO, interacts with a neoepitope
generated at the N-terminus of the caspase small subunit following activation.
Therefore, BIR2 uses a two-site interaction mechanism to achieve high
specificity and potency for inhibition. Moreover, for caspase-7, the precise
location of the activating cleavage is critical for subsequent inhibition. Since
apical caspases utilize this cleavage site differently, it is predicted that the
origin of the death stimulus should dictate the efficiency of inhibition by XIAP (Scott, 2005).
The fundamental mechanism of specific protein interactions is usually
conserved during protein evolution. According to conservation of mechanism, the
two units of XIAP that inhibit caspases should preserve a fundamental
interaction strategy. On the basis of structural studies, this concept could be
questioned. The key elements of caspase-9 inhibition by BIR3 are the IBM
interacting groove and the C-terminal helix. In contrast,
the key element of caspase-3 and -7 inhibition by BIR2 seems to be the
completely nonconserved N-terminal linker region.
The most conserved surface structure of BIR domains
is the IBM interacting groove. It is found on many BIR domains including the
BIR2 and BIR3 of XIAP, and the BIR1 and BIR2 of an ortholog in Drosophila
melanogaster, DIAP1. The surface groove of DIAP1 BIR2 is involved in binding and
ubiquitination of Dronc, the initiator caspase in flies.
In addition, the IBM interacting groove of DIAP1 BIR1 is
absolutely required for inhibition of the executioner caspase DrICE by an
unknown mechanism. It is suggested that the IBM interacting groove is a
conserved interaction element of BIR domains and that for XIAP BIR2 it confers
tight inhibition of caspase-3 and -7 by providing a second binding site (Scott, 2005).
Both BIR2 and BIR3 inhibit their target caspases by a two-site
interaction mechanism. They have conserved a functional IBM interacting groove
that participates in inhibition by binding neoepitopes revealed following
activation of their target enzymes. This interaction, primarily a docking
contact, represents the conserved mechanism and also provides a platform for
regulation by antagonists Smac/DIABLO and HtrA2. The primary inhibition site,
however, is mechanistically different for each domain: blocking the active site
in caspase-3 and -7, or dissociating the dimer of caspase-9. It is far from
clear how the inhibitory mechanism diverged. It is much clearer that these
distinct mechanisms direct the exquisite specificity that allows XIAP BIR
domains to target selectively individual caspases in a way that other inhibitory
strategies, both natural and artificial have yet to achieve (Scott, 2005).
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