scholarly journals Crystal structure of caspase recruiting domain (CARD) of apoptosis repressor with CARD (ARC) and its implication in inhibition of apoptosis

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Tae-ho Jang ◽  
Seong Hyun Kim ◽  
Jae-Hee Jeong ◽  
Sunghwan Kim ◽  
Yeon-Gil Kim ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Death Domain ◽  
Apoptosis Pathway ◽  
Effector Domains ◽  
Inhibitory Function ◽  
Rich Domain ◽  
Extrinsic Apoptosis ◽  
Optimal Target ◽  
Death Effector ◽  
Disc Formation

Abstract Apoptosis repressor with caspase recruiting domain (ARC) is a multifunctional inhibitor of apoptosis that is unusually over-expressed or activated in various cancers and in the state of the pulmonary hypertension. Therefore, ARC might be an optimal target for therapeutic intervention. Human ARC is composed of two distinct domains, N-terminal caspase recruiting domain (CARD) and C-terminal P/E (proline and glutamic acid) rich domain. ARC inhibits the extrinsic apoptosis pathway by interfering with DISC formation. ARC CARD directly interacts with the death domains (DDs) of Fas and FADD, as well as with the death effector domains (DEDs) of procaspase-8. Here, we report the first crystal structure of the CARD domain of ARC at a resolution of 2.4 Å. Our structure was a dimer with novel homo-dimerization interfaces that might be critical to its inhibitory function. Interestingly, ARC did not exhibit a typical death domain fold. The sixth helix (H6), which was detected at the typical death domain fold, was not detected in the structure of ARC, indicating that H6 may be dispensable for the function of the death domain superfamily.

Crystal structure of the death effector domains of caspase-8

2015 ◽  
Vol 463 (3) ◽  
pp. 297-302 ◽  
Author(s):  
Chen Shen ◽  
Hong Yue ◽  
Jianwen Pei ◽  
Xiaomin Guo ◽  
Tao Wang ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Caspase 8 ◽  
Effector Domains ◽  
Death Effector

scholarly journals The flip side of FLIP

2004 ◽  
Vol 382 (2) ◽  
Author(s):  
Marcus E. PETER
Keyword(s):  
Mammalian Cells ◽  
Caspase 8 ◽  
Death Domain ◽  
Extrinsic Pathway ◽  
Inhibitory Protein ◽  
Apoptosis Pathway ◽  
Surface Receptors ◽  
Biochemical Journal ◽  
Initiator Caspases ◽  
Extrinsic Apoptosis

Two major pathways regulate apoptosis induction in mammalian cells. In the extrinsic pathway, apoptosis is induced through specialized surface receptors, whereas in the intrinsic pathway, apoptosis is induced from within the cell, mainly through activation of mitochondria. Shortly after the major mediators of the extrinsic apoptosis pathway, the initiator caspases-8 and -10, were identified, c-FLIP [FLICE-like inhibitory protein; FLICE is FADD (Fas-associated death domain protein)-like interleukin-1β-converting enzyme], a catalytically inactive caspase-8/-10 homologue, was reported. Whether this structure acts as an inhibitor or promoter of the extrinsic apoptosis pathway has been the subject of much debate. In this issue of the Biochemical Journal, Boatright et al. provide further evidence for the long splice form of c-FLIP (c-FLIPL) being an activator of caspase-8/-10, and demonstrate that the resulting heterodimer is enzymically active with a substrate specificity identical with that of the caspase-8 homodimer. Our understanding of the regulators of the extrinsic apoptosis signalling pathway biochemically may provide the means to design drugs to correct the imbalance between apoptosis and proliferation, as found in many diseases.

scholarly journals Platelets express adaptor proteins of the extrinsic apoptosis pathway and can activate caspase-8

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0244848
Author(s):  
Nadine Goelz ◽  
Julia J. M. Eekels ◽  
Milica Pantic ◽  
Christoph T. Kamber ◽  
Oliver Speer ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Caspase 3 ◽  
Human Platelets ◽  
Death Domain ◽  
Extrinsic Pathway ◽  
Apoptosis Pathway ◽  
Extrinsic Apoptosis ◽  
Necrosis Factor

Background Apoptotic pathways in platelets are important for their survival and function. Platelet apoptosis may be involved in the pathogenesis of immune thrombocytopenia (ITP), an autoimmune-mediated disease. In contrast to the intrinsic apoptosis pathway, not much is known about the extrinsic pathway mechanisms in platelets. Objectives To investigate the expression of proteins involved in the extrinsic apoptosis pathway, including the death receptors, adaptor and regulator proteins in human platelets. To determine a possible trigger of the extrinsic apoptosis pathway in platelets. Methods To investigate the expression of key markers of the extrinsic pathway we used targeted immunofluorescence and flow cytometry assays. To study their expression and interaction we performed Western blotting and co-immunoprecipitation. Treated platelets with different apoptosis triggers were subjected to flow cytometry. Results We could identify the protein expression of the pro-apoptotic proteins TRADD (Tumor Necrosis Factor Receptor type 1- Associated DEATH Domain protein), TRAF2/5, (TNF Associated Factor) and DEDAF (Death Effector Domain- Associated Factor), FADD (Fas-Associated protein with death domain) as well as the anti-apoptotic proteins DJ-1 (Deglycase 1) and c-FLIP in human platelets. ABT-737 treatment induced a disruption in the co-localization of DJ-1 with FADD. Platelets treated with ABT-737 showed an activation in caspase-3 and -8. The exposure to TNF (Tumor Necrosis Factor), FasL (Fas ligand), and TWEAK or to plasma derived from ITP patients, did not lead to changes in caspase-3 and -8 activation in platelets. Conclusions Human platelets express some proteins of the extrinsic apoptosis pathway which can be modulated only by ABT-737 treatment. However so far, no other apoptosis trigger or interaction with an external receptor have been yet identified.

scholarly journals Progress in understanding the role of lncRNA in programmed cell death

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Na Jiang ◽  
Xiaoyu Zhang ◽  
Xuejun Gu ◽  
Xiaozhuang Li ◽  
Lei Shang
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Molecular Mechanisms ◽  
Membrane Receptors ◽  
Gene Expressions ◽  
Apoptosis Pathway ◽  
Stem Cell Pluripotency ◽  
Extrinsic Apoptosis ◽  
Related Proteins ◽  
Cycle Regulation

AbstractLong non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides but not translated into proteins. LncRNAs regulate gene expressions at multiple levels, such as chromatin, transcription, and post-transcription. Further, lncRNAs participate in various biological processes such as cell differentiation, cell cycle regulation, and maintenance of stem cell pluripotency. We have previously reported that lncRNAs are closely related to programmed cell death (PCD), which includes apoptosis, autophagy, necroptosis, and ferroptosis. Overexpression of lncRNA can suppress the extrinsic apoptosis pathway by downregulating of membrane receptors and protect tumor cells by inhibiting the expression of necroptosis-related proteins. Some lncRNAs can also act as competitive endogenous RNA to prevent oxidation, thereby inhibiting ferroptosis, while some are known to activate autophagy. The relationship between lncRNA and PCD has promising implications in clinical research, and reports have highlighted this relationship in various cancers such as non-small cell lung cancer and gastric cancer. This review systematically summarizes the advances in the understanding of the molecular mechanisms through which lncRNAs impact PCD.

Deterministic Modeling in Medicine

2009 ◽  
pp. 74-96
Author(s):  
Elisabeth Maschke-Dutz
Keyword(s):  
Metabolic Control ◽  
Data Exchange ◽  
Time Course ◽  
Metabolic Control Analysis ◽  
Test Case ◽  
Control Analysis ◽  
Mathematical Methods ◽  
Apoptosis Pathway ◽  
Biochemical Systems ◽  
Extrinsic Apoptosis

In this chapter basic mathematical methods for the deterministic kinetic modeling of biochemical systems are described. Mathematical analysis methods, the respective algorithms, and appropriate tools and resources, as well as established standards for data exchange, model representations and definitions are presented. The methods comprise time-course simulations, steady state search, parameter scanning, and metabolic control analysis among others. An application is demonstrated using a test case model that describes parts of the extrinsic apoptosis pathway and a small example network demonstrates an implementation of metabolic control analysis.

scholarly journals Unsaturated fatty acyl recognition by Frizzled receptors mediates dimerization upon Wnt ligand binding

2017 ◽  
Vol 114 (16) ◽  
pp. 4147-4152 ◽  
Author(s):  
Aaron H. Nile ◽  
Susmith Mukund ◽  
Karen Stanger ◽  
Weiru Wang ◽  
Rami N. Hannoush
Keyword(s):  
Crystal Structure ◽  
Fatty Acid ◽  
Wnt Signaling ◽  
Bone Growth ◽  
Cell Activity ◽  
Fatty Acyl ◽  
Lipid Binding ◽  
Receptor Expression ◽  
Rich Domain ◽  
Binding Groove

Frizzled (FZD) receptors mediate Wnt signaling in diverse processes ranging from bone growth to stem cell activity. Moreover, high FZD receptor expression at the cell surface contributes to overactive Wnt signaling in subsets of pancreatic, ovarian, gastric, and colorectal tumors. Despite the progress in biochemical understanding of Wnt–FZD receptor interactions, the molecular basis for recognition of Wnt cis-unsaturated fatty acyl groups by the cysteine-rich domain (CRD) of FZD receptors remains elusive. Here, we determined a crystal structure of human FZD7 CRD unexpectedly bound to a 24-carbon fatty acid. We also report a crystal structure of human FZD5 CRD bound to C16:1 cis-Δ9 unsaturated fatty acid. Both structures reveal a dimeric arrangement of the CRD. The lipid-binding groove exhibits flexibility and spans both monomers, adopting a U-shaped geometry that accommodates the fatty acid. Re-evaluation of the published mouse FZD8 CRD structure reveals that it also shares the same architecture as FZD5 and FZD7 CRDs. Our results define a common molecular mechanism for recognition of the cis-unsaturated fatty acyl group, a necessary posttranslational modification of Wnts, by multiple FZD receptors. The fatty acid bridges two CRD monomers, implying that Wnt binding mediates FZD receptor dimerization. Our data uncover possibilities for the arrangement of Wnt–FZD CRD complexes and shed structural insights that could aide in the identification of pharmacological strategies to modulate FZD receptor function.

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