Delineating the role of c-FLIP/NEMO interaction in the CD95 network via rational design of molecular probes

Autor: Max Richter, Johannes Espe, Inna N. Lavrik, Laura K. Hillert, M. Bollmann, Jörn H. Buchbinder, V. A. Ivanisenko, Nikita V. Ivanisenko
Rok vydání: 2019
Předmět:
0106 biological sciences
congenital
hereditary
and neonatal diseases and abnormalities
lcsh:QH426-470
lcsh:Biotechnology
In silico
Gene regulatory network
CASP8 and FADD-Like Apoptosis Regulating Protein
C-FLIP
Computational biology
Biology
Proteomics
01 natural sciences
NF-κB
Conserved sequence
03 medical and health sciences
chemistry.chemical_compound
NEMO
lcsh:TP248.13-248.65
Genetics
Humans
Protein Interaction Domains and Motifs
Homology modeling
Amino Acid Sequence
fas Receptor
skin and connective tissue diseases
Protein Structure
Quaternary
030304 developmental biology
Evolutionary conservation
0303 health sciences
Research
Rational design
NF-kappa B
Computational Biology
I-kappa B Kinase
lcsh:Genetics
chemistry
Molecular Probes
Death receptor network
Sequence Alignment
Function (biology)
V-FLIP
010606 plant biology & botany
Biotechnology
Signal Transduction
Zdroj: BMC Genomics
BMC Genomics, Vol 20, Iss S3, Pp 1-12 (2019)
ISSN: 1471-2164
Popis: 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 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 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.
Databáze: OpenAIRE
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