scholarly journals Peroxiredoxin 6 interferes with TRAIL-induced death-inducing signaling complex formation by binding to death effector domain caspase

2010 ◽  
Vol 18 (3) ◽  
pp. 405-414 ◽  
Author(s):  
H Choi ◽  
J-W Chang ◽  
Y-K Jung
Keyword(s):  
Complex Formation ◽  
Peroxiredoxin 6 ◽  
Effector Domain ◽  
Death Effector Domain ◽  
Signaling Complex ◽  
Death Effector

scholarly journals PEA-15 C-Terminal Tail Allosterically Modulates Death-Effector Domain Conformation and Facilitates Protein–Protein Interactions

2019 ◽  
Vol 20 (13) ◽  
pp. 3335
Author(s):  
Sergio L. Crespo-Flores ◽  
Andres Cabezas ◽  
Sherouk Hassan ◽  
Yufeng Wei
Keyword(s):  
Protein Interactions ◽  
De Novo ◽  
Free Form ◽  
Docking Site ◽  
Death Domain ◽  
Protein Protein Interactions ◽  
Effector Domain ◽  
Death Effector Domain ◽  
Signaling Complex ◽  
Death Effector

Phosphoprotein enriched in astrocytes, 15 kDa (PEA-15) exerts its regulatory roles on several critical cellular pathways through protein–protein interactions depending on its phosphorylation states. It can either inhibit the extracellular signal-regulated kinase (ERK) activities when it is dephosphorylated or block the assembly of death-inducing signaling complex (DISC) and the subsequent activation of apoptotic initiator, caspase-8, when it is phosphorylated. Due to the important roles of PEA-15 in regulating these pathways that lead to opposite cellular outcomes (cell proliferation vs. cell death), we proposed a phosphostasis (phosphorylation homeostasis) model, in which the phosphorylation states of the protein are vigorously controlled and regulated to maintain a delicate balance. The phosphostasis gives rise to the protective cellular functions of PEA-15 to preserve optimum cellular conditions. In this article, using advanced multidimensional nuclear magnetic resonance (NMR) techniques combined with a novel chemical shift (CS)-Rosetta algorithm for de novo protein structural determination, we report a novel conformation of PEA-15 death-effector domain (DED) upon interacting with ERK2. This new conformation is modulated by the irregularly structured C-terminal tail when it first recognizes and binds to ERK2 at the d-peptide recruitment site (DRS) in an allosteric manner, and is facilitated by the rearrangement of the surface electrostatic and hydrogen-bonding interactions on the DED. In this ERK2-bound conformation, three of the six helices (α2, α3, and α4) comprising the DED reorient substantially in comparison to the free-form structure, exposing key residues on the other three helices that directly interact with ERK2 at the DEF-docking site (docking site for ERK, FxF) and the activation loop. Additionally, we provide evidence that the phosphorylation of the C-terminal tail leads to a distinct conformation of DED, allowing efficient interactions with Fas-associated death domain (FADD) protein at the DISC. Our results substantiate the allosteric regulatory roles of the C-terminal tail in modulating DED conformation and facilitating protein–protein interactions of PEA-15.

scholarly journals Stoichiometry of the CD95 Death-Inducing Signaling Complex: Experimental and Modeling Evidence for a Death Effector Domain Chain Model

2012 ◽  
Vol 47 (2) ◽  
pp. 306-319 ◽  
Author(s):  
Kolja Schleich ◽  
Uwe Warnken ◽  
Nicolai Fricker ◽  
Selcen Öztürk ◽  
Petra Richter ◽  
...  
Keyword(s):  
Chain Model ◽  
Effector Domain ◽  
Death Effector Domain ◽  
Signaling Complex ◽  
Death Effector

scholarly journals Huntingtin Interacting Protein 1 Induces Apoptosis via a Novel Caspase-dependent Death Effector Domain

2000 ◽  
Vol 275 (52) ◽  
pp. 41299-41308 ◽  
Author(s):  
Abigail S. Hackam ◽  
Ayman S. Yassa ◽  
Roshni Singaraja ◽  
Martina Metzler ◽  
Claire-Anne Gutekunst ◽  
...  
Keyword(s):  
Interacting Protein ◽  
Effector Domain ◽  
Death Effector Domain ◽  
Huntingtin Interacting Protein 1 ◽  
Death Effector ◽  
Huntingtin Interacting Protein

scholarly journals Caspase- and Serine Protease-dependent Apoptosis by the Death Domain of FADD in Normal Epithelial Cells

2003 ◽  
Vol 14 (1) ◽  
pp. 67-77 ◽  
Author(s):  
Jacqueline Thorburn ◽  
Laura M. Bender ◽  
Michael J. Morgan ◽  
Andrew Thorburn
Keyword(s):  
Epithelial Cells ◽  
Serine Protease ◽  
Death Domain ◽  
Cell Type ◽  
Normal Prostate ◽  
Effector Domain ◽  
Death Effector Domain ◽  
Prostate Epithelial Cells ◽  
Cell Type Specific ◽  
Death Effector

The adapter protein FADD consists of two protein interaction domains: a death domain and a death effector domain. The death domain binds to activated death receptors such as Fas, whereas the death effector domain binds to procaspase 8. An FADD mutant, which consists of only the death domain (FADD-DD), inhibits death receptor–induced apoptosis. FADD-DD can also activate a mechanistically distinct, cell type–specific apoptotic pathway that kills normal but not cancerous prostate epithelial cells. Here, we show that this apoptosis occurs through activation of caspases 9, 3, 6, and 7 and a serine protease. Simultaneous inhibition of caspases and serine proteases prevents FADD-DD–induced death. Inhibition of either pathway alone does not prevent cell death but does affect the morphology of the dying cells. Normal prostate epithelial cells require both the caspase and serine protease inhibitors to efficiently prevent apoptosis in response to TRAIL. In contrast, the serine protease inhibitor does not affect TRAIL-induced death in prostate tumor cells suggesting that the FADD-DD–dependent pathway can be activated by TRAIL. This apoptosis pathway is activated in a cell type–specific manner that is defective in cancer cells, suggesting that this pathway may be targeted during cancer development.

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