Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.4.22.60 (
caspase-7
)
920
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The inhibitor of apoptosis proteins (IAP) regulates cell death by inhibiting caspases. The region of X-linked (X) IAP containing the second baculovirus IAP repeat domain (BIR2) is sufficient for inhibiting caspase-3 and -7. In this study, we found that the modes of inhibition of these two caspases were different: caspase-3 is inhibited in a competitive manner whereas
caspase-7
inhibition occurs through a mixed competitive and noncompetitive mechanism. Binding assays revealed that the inhibition of caspase-3 by XIAP was totally dependent on the interaction between the active site of caspase-3 and the linker region between the
BIR1
and BIR2 domains of XIAP. In contrast, the active site and the NH(2)-terminal region of
caspase-7
bound to the linker region and the BIR2, respectively. Moreover the BIR2 with a mutated linker region, which inhibited caspase-3 very weakly, still bound to and inhibited
caspase-7
. Furthermore, a chimeric
caspase-7
/3 comprising the NH(2)-terminal portion of
caspase-7
and COOH-terminal portion of caspase-3 was inhibited by XIAP by a mixed competitive and noncompetitive mechanism. Our results suggest that the linker region between
BIR1
and BIR2 domains is responsible for active site-directed, competitive inhibition of both caspase-3 and -7, whereas the BIR2 itself is involved in noncompetitive inhibition of
caspase-7
.
...
PMID:X-linked inhibitor of apoptosis protein (XIAP) inhibits caspase-3 and -7 in distinct modes. 1135 76
The ability of the irreversibly denatured XIAP-BIR2 domain versus the native protein in inhibition of executioner caspase-3 and -7 was investigated. The denatured protein that lacked the physical characteristics of the native protein inhibited
caspase-7
, while failing to inhibit caspase-3. Furthermore, the kinetics of association of the denatured protein with
caspase-7
decreased substantially suggesting that the exposure of the linker is reduced. This was further confirmed by the decreased level of proteolysis at the linker by trypsin for the denatured protein. These results suggest that the essential moiety of the XIAP involved in inhibition is the linker joining
BIR1
to BIR2 and that the BIR2 plays a marginal role in inhibition.
...
PMID:BIR2 domain of XIAP plays a marginal role in inhibition of executioner caspases. 2006 Apr 11
