SECUAH 2021

dianas | Vol 9 No 1 | marzo 2020 | e202003

Computational approaches to the structure and activation mechanism of Toll-like receptor 4

Alejandra Matamoros-Recio, Joan Guzmán-Caldentey, Sonsoles Martín-Santamaría

Centro de Investigaciones Biológicas Margarita Salas, CSIC, C/ Ramiro de Maeztu, 9, 28040 Madrid, Spain

alejandra.matamoros@cib.csic.es

V Congreso de Señalización Celular, SECUAH 2020.
16-18 de marzo, 2020. Universidad de Alcalá. Alcalá de Henares, Madrid. España.

Keywords: toll-like receptors; TLR4; plasma membrane; computational studies; signal transduction

Abstract

Toll-like receptors (TLRs) are pattern recognition receptors involved in the innate immunity. In particular, TLR4 binds to lipopolysaccharides, a membrane constituent of Gram-negative bacteria, and together with MD-2 protein, forms a heterodimeric complex which leads to the activation of the innate immune system response. TLR4 activation has been associated with certain autoimmune diseases, noninfectious inflammatory disorders, and neuropathic pain. Consequently, TLR4 has risen as a promising therapeutic target, and design of TLR4 modulating drugs constitutes a highly relevant and active research area. Specific molecular features of extracellular, transmembrane and cytoplasmic domains of TLR4 are crucial for coordinating the complex innate immune signaling pathway. Although X-ray, NMR and biological structural data is currently available for the independent TLR4 domains, the structure fragments only provide a partial view, because full-length proteins are flexible entities and dynamics play a key role in their functionality. Therefore, many structural and dynamical features of the TLR4 mode of action remain largely unknown. On this basis, computational studies of the different independent domains composing the TLR4 are undertaken in our research group, using homology modeling, protein-protein docking, and molecular dynamics simulations, to understand the differential domain organization of TLR4 in a wide range of membrane-aqueous environments, including liquid-disorder and liquid-order membrane models, to account for the TLR4 recruitment in lipid-rafts over activation. Our final goal is, from the information gathered in our studies, to propose a full TLR4/MD-2 dimer model that explain most of the molecular information known to date increasing the current knowledge of the complex mechanism of receptor activation, and adaptor recruitment in the innate immune signaling pathway, and make use of this new knowledge to design novel TLR4 modulators and probes.