| Project/Area Number |
11670655
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Neurology
|
|---|
| Research Institution | RIKEN |
|---|
Principal Investigator |
TAKAHASHI Ryosuke RIKEN Brain Science Insutitute Lab. Motor System Neurodegenaration, Head, 運動系神経変性研究チーム, チームリーダー(研究職) (90216771)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
SUZUKI Yasuyuki RIKEN Brain Science Insutitute.Lab. Motor System Neurodegenaration, Staff Scientist, 運動系神経変性研究チーム, 研究員 (40321773)
|
|---|
| Project Period (FY) |
1999 – 2000
|
| Project Status |
Completed (Fiscal Year 2001)
|
| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2000: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1999: ¥2,100,000 (Direct Cost: ¥2,100,000)
|
|---|
| Keywords | IAP / caspase / BIR / Ubiquitin ligase / RING finger / mitochondria / HtrA2 / Omi / アポトーシス / IAP / XIAP / カスペース3 / カスペース7 / RINGフィンガー / カスペース-7 / カスペース-3 / 競合的阻害剤 / 非競合的阻害剤 |
|---|
| Research Abstract |
X-linked inhibitor of apoptosis protein (XIAP), a member of IAP fatmly, is an endogenous caspase inhibitor and has three tandem repeats of BIR sequences at its NH2-terminus and a RlNG finger motif at its COOH terminus. BIR2 domain is responsible for XIAP mediated caspase-3/-7.We found that caspase-3 is inhibited in a competitive manner while caspase-7 inhibition occurs through a mixed competitive and noncompetitive mechanism. Further analyses revealed that the linker region between BIRI 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 (J Biol Chem, 2001). Next, we found that XIAP acts as a ubiquitin-protein ligase for caspase-3.We demonstrated that the ubiquitin-protein ligase activity of XIAP promotes the degradation of caspase-3, which enhances its anti-apoptotic effect (Proc Natl Acad Sci, 2001). Finally, we found that a serine protease termed HtrA2/0mi is released from the mitochondria upon apoptotic stimuli, and binds to and inhibits XIAP (Mol. Cell, 2OOl).
|
