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1. Introduction
2. Apoptosis in C. elegans
3. Two pathways of apoptosis in mammals
4. Intrinsic apoptosis
5. IAPs
6. SMAC involvement in apoptosis
7. Apoptosis pathways in mammals and Drozophila
8. The essential N-terminal role of SMAC
9. Illustration of SMAC
10. Crystal structure of a variant of SMAC molecule
11. XIAP-BIR3 binding amino acids
12. Binding of SMAC to a conserved pocket on BIR
13. Caspase-9 binds to IAPs
14. Inhibition of caspase-9 by binding of XIAP
15. A conserved active site conformation of caspases
16. XIAP sequesters caspase-9 in a monomeric state
17. CASP9 and SMAC bind to the same BIR domain
18. IAPs inhibition of effector caspases
19. Crystal structures of CASP7 and 3 bound to XIAP
20. Structure of mature caspase-3 bound to BIR2
21. Mechanism of inhibition by XIAP
22. How can SMAC counter the inhibition?
23. Activation of effector and initiator caspases
24. A conserved active site conformation of caspases
25. Caspase-7 zymogen conformation
26. Active site conformation distortion in the zymogen
27. Initiator caspases
28. Intiator caspases activation by large complexed
29. An assembly apoptosome model with Apaf-1
30. Cryo-EM structure of Dark/Hac-1/Dapaf-1
31. C. elegans genetically defined apoptosis pathway
32. Biochemistry of the apoptotic pathway
33. How does CED-9 negatively regulate CED-4?
34. CED-4-CED-9 complex stoichiometry
35. CED-4-CED-9 complex
36. CED-4 binds to one ATP and one Mg ion
37. How does CED-9 inhibit CED-4?
38. Free CED-4 exhibits higher molecular weight
39. Free CED-4 is a tetramer by EM
40. Mutagenesis disruption of CED-4 oligomerization
41. CED-4 tetramer only activates CED-3
42. CED-9 blocks CED-4 from further dimerization
43. EGL-1 release CED-4 from inhibitory complex
44. Binding of CED-9 by EGL-1 C-terminus
45. CED-9-EGL-1 exists as a single folding unit
46. EGL-1 induces conformation changes in CED-9
47. CED-4 and EGL-1 bind to different sites of CED-9
48. EGL-1 displaces CED-9 from the complex
49. EGL-1 binds to CED-9 with higher affinity
50. Current model of the linear PCD pathway
51. Apoptosis pathway diagram in three species
52. Acknowledgments

Topics Covered

• Structural mechanism of IAP recognition by Smac/DIABLO
• Structural mechanism of caspase-9 inhibition by XIAP-BIR3
• Structural mechanism of effector caspase inhibition by XIAP
• Structural mechanism of initiator caspase activation
• Structural biology of the apoptosome
• Structural biology of the programmed cell death pathway in C. elegans

Links

Series:

• Apoptosis

Categories:

• Biochemistry
• Cell Biology

Therapeutic Areas:

• Immunology & Inflammation

Talk Citation

Publication History

• Published on October 1, 2007

Financial Disclosures

• Prof. Yigong Shi has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.