Investigating the effect of key mutations on the conformational dynamics of toll-like receptor dimers through molecular dynamics simulations and protein structure networks
| Autor: | Jarjapu Mahita, Ramanathan Sowdhamini |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Protein Conformation Mutant Molecular Dynamics Simulation medicine.disease_cause Biochemistry 03 medical and health sciences Protein structure Structural Biology medicine Humans Point Mutation Protein Interaction Domains and Motifs Protein Interaction Maps Receptor Molecular Biology Mutation Toll-like receptor Protein Stability Chemistry Toll-Like Receptors Ligand (biochemistry) Toll-Like Receptor 1 Toll-Like Receptor 2 Toll-Like Receptor 3 Cell biology Molecular Docking Simulation Toll-Like Receptor 4 030104 developmental biology TLR3 Protein Multimerization Signal transduction Hydrophobic and Hydrophilic Interactions |
| Zdroj: | Proteins: Structure, Function, and Bioinformatics. 86:475-490 |
| ISSN: | 0887-3585 |
| DOI: | 10.1002/prot.25467 |
| Popis: | The Toll-like receptors (TLRs) are critical components of the innate immune system due to their ability to detect conserved pathogen-associated molecular patterns, present in bacteria, viruses, and other microorganisms. Ligand detection by TLRs leads to a signaling cascade, mediated by interactions among TIR domains present in the receptors, the bridging adaptors and sorting adaptors. The BB loop is a highly conserved region present in the TIR domain and is crucial for mediating interactions among TIR domain-containing proteins. Mutations in the BB loop of the Toll-like receptors, such as the A795P mutation in TLR3 and the P712H mutation (Lpsd mutation) in TLR4, have been reported to disrupt or alter downstream signaling. While the phenotypic effect of these mutations is known, the underlying effect of these mutations on the structure, dynamics and interactions with other TIR domain-containing proteins is not well understood. Here, we have attempted to investigate the effect of the BB loop mutations on the dimer form of TLRs, using TLR2 and TLR3 as case studies. Our results based on molecular dynamics simulations, protein-protein interaction analyses and protein structure network analyses highlight significant differences between the dimer interfaces of the wild-type and mutant forms and provide a logical reasoning for the effect of these mutations on adaptor binding to TLRs. Furthermore, it also leads us to propose a hypothesis for the differential requirement of signaling and bridging adaptors by TLRs. This could aid in further understanding of the mechanisms governing such signaling pathways. |
| Databáze: | OpenAIRE |
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