In silico approach to inhibition of signaling pathways of Toll-like receptors 2 and 4 by ST2L

TitleIn silico approach to inhibition of signaling pathways of Toll-like receptors 2 and 4 by ST2L
Publication TypeJournal Article
Year of Publication2011
AuthorsBasith S, Manavalan B, Govindaraj RG, Choi S
JournalPLoS ONE
Date Published2011
KeywordsAmino Acid Sequence, Computational Biology, Humans, Membrane Transport Proteins, Molecular Dynamics Simulation, Molecular Sequence Data, Myelin and Lymphocyte-Associated Proteolipid Proteins, Myelin Proteins, Myeloid Differentiation Factor 88, Protein Multimerization, Protein Stability, Protein Structure, Quaternary, Protein Structure, Tertiary, Proteolipids, Receptors, Cell Surface, Sequence Alignment, Signal Transduction, Toll-Like Receptor 2, Toll-Like Receptor 4, Toll-Like Receptor 6

Toll-like receptors (TLRs) activate a potent immunostimulatory response. There is clear evidence that overactivation of TLRs leads to infectious and inflammatory diseases. Recent biochemical studies have shown that the membrane-bound form of ST2 (ST2L), a member of the Toll-like/IL-1 receptor superfamily, negatively regulates MyD88-dependent TLR signaling pathways by sequestrating the adapters MyD88 and Mal (TIRAP). Specifically, ST2L attenuates the recruitment of Mal and MyD88 adapters to their receptors through its intracellular TIR domain. Thus, ST2L is a potent molecule that acts as a key regulator of endotoxin tolerance and modulates innate immunity. So far, the inhibitory mechanism of ST2L at the molecular level remains elusive. To develop a working hypothesis for the interactions between ST2L, TLRs (TLR1, 2, 4, and 6), and adapter molecules (MyD88 and Mal), we constructed three-dimensional models of the TIR domains of TLR4, 6, Mal, and ST2L based on homology modeling. Since the crystal structures of the TIR domains of TLR1, 2 as well as the NMR solution structure of MyD88 are known, we utilized these structures in our analysis. The TIR domains of TLR1, 2, 4, 6, MyD88, Mal and ST2L were subjected to molecular dynamics (MD) simulations in an explicit solvent environment. The refined structures obtained from the MD simulations were subsequently used in molecular docking studies to probe for potential sites of interactions. Through protein-protein docking analysis, models of the essential complexes involved in TLR2 and 4 signaling and ST2L inhibiting processes were developed. Our results suggest that ST2L may exert its inhibitory effect by blocking the molecular interface of Mal and MyD88 adapters mainly through its BB-loop region. Our predicted oligomeric signaling models may provide a basis for the understanding of the assembly process of TIR domain interactions, which has thus far proven to be difficult via in vivo studies.

Alternate JournalPLoS ONE

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