Delineating the role of c-FLIP/NEMO interaction in the CD95 network via rational design of molecular probes.
Amino Acid Sequence
CASP8 and FADD-Like Apoptosis Regulating Protein
/ metabolism
Computational Biology
Humans
I-kappa B Kinase
/ metabolism
Molecular Probes
NF-kappa B
/ metabolism
Protein Interaction Domains and Motifs
Protein Structure, Quaternary
Sequence Alignment
Signal Transduction
fas Receptor
/ metabolism
C-FLIP
Death receptor network
Evolutionary conservation
Homology modeling
In silico
NEMO
NF-κB
V-FLIP
Journal
BMC genomics
ISSN: 1471-2164
Titre abrégé: BMC Genomics
Pays: England
ID NLM: 100965258
Informations de publication
Date de publication:
08 May 2019
08 May 2019
Historique:
entrez:
10
12
2019
pubmed:
10
12
2019
medline:
6
2
2020
Statut:
epublish
Résumé
Structural homology modeling supported by bioinformatics analysis plays a key role in uncovering new molecular interactions within gene regulatory networks. Here, we have applied this powerful approach to analyze the molecular interactions orchestrating death receptor signaling networks. In particular, we focused on the molecular mechanisms of CD95-mediated NF-κB activation and the role of c-FLIP/NEMO interaction in the induction of this pathway. To this end, we have created the homology model of the c-FLIP/NEMO complex using the reported structure of the v-FLIP/NEMO complex, and rationally designed peptides targeting this complex. The designed peptides were based on the NEMO structure. Strikingly, the experimental in vitro validation demonstrated that the best inhibitory effects on CD95-mediated NF-κB activation are exhibited by the NEMO-derived peptides with the substitution D242Y of NEMO. Furthermore, we have assumed that the c-FLIP/NEMO complex is recruited to the DED filaments formed upon CD95 activation and validated this assumption in silico. Further insight into the function of c-FLIP/NEMO complex was provided by the analysis of evolutionary conservation of interacting regions which demonstrated that this interaction is common in distinct mammalian species. Taken together, using a combination of bioinformatics and experimental approaches we obtained new insights into CD95-mediated NF-κB activation, providing manifold possibilities for targeting the death receptor network.
Sections du résumé
BACKGROUND
BACKGROUND
Structural homology modeling supported by bioinformatics analysis plays a key role in uncovering new molecular interactions within gene regulatory networks. Here, we have applied this powerful approach to analyze the molecular interactions orchestrating death receptor signaling networks. In particular, we focused on the molecular mechanisms of CD95-mediated NF-κB activation and the role of c-FLIP/NEMO interaction in the induction of this pathway.
RESULTS
RESULTS
To this end, we have created the homology model of the c-FLIP/NEMO complex using the reported structure of the v-FLIP/NEMO complex, and rationally designed peptides targeting this complex. The designed peptides were based on the NEMO structure. Strikingly, the experimental in vitro validation demonstrated that the best inhibitory effects on CD95-mediated NF-κB activation are exhibited by the NEMO-derived peptides with the substitution D242Y of NEMO. Furthermore, we have assumed that the c-FLIP/NEMO complex is recruited to the DED filaments formed upon CD95 activation and validated this assumption in silico. Further insight into the function of c-FLIP/NEMO complex was provided by the analysis of evolutionary conservation of interacting regions which demonstrated that this interaction is common in distinct mammalian species.
CONCLUSIONS
CONCLUSIONS
Taken together, using a combination of bioinformatics and experimental approaches we obtained new insights into CD95-mediated NF-κB activation, providing manifold possibilities for targeting the death receptor network.
Identifiants
pubmed: 31815628
doi: 10.1186/s12864-019-5539-y
pii: 10.1186/s12864-019-5539-y
pmc: PMC6900753
doi:
Substances chimiques
CASP8 and FADD-Like Apoptosis Regulating Protein
0
IKBKG protein, human
0
Molecular Probes
0
NF-kappa B
0
fas Receptor
0
I-kappa B Kinase
EC 2.7.11.10
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
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