A thermodynamic funnel drives bacterial lipopolysaccharide transfer in the TLR4 pathway

Huber, Roland G., Berglund, Nils A., Kargas, Vasileios, Marzinek, Jan K., Holdbrook, Daniel A., Khalid, Syma, Piggot, Thomas J., Schmidtchen, Artur and Bond, Peter J. (2018) A thermodynamic funnel drives bacterial lipopolysaccharide transfer in the TLR4 pathway. Structure, 26 (8), 1151-1161. (doi:10.1016/j.str.2018.04.007).

Abstract

The Gram-negative bacterial outer membrane contains lipopolysaccharide, which potently stimulates the mammalian innate immune response. This involves a relay of specialized complexes culminating in transfer of lipopolysaccharide from CD14 to Toll-like receptor 4 (TLR4) and its co-receptor MD-2 on the cell surface, leading to activation of downstream inflammatory responses. In this study we develop computational models to trace the TLR4 cascade in near-atomic detail. We demonstrate through rigorous thermodynamic calculations that lipopolysaccharide molecules traversing the receptor cascade fall into a thermodynamic funnel. An affinity gradient for lipopolysaccharide is revealed upon extraction from aggregates or realistic bacterial outer membrane models and transfer through CD14 to the terminal TLR4/MD-2 receptor-co-receptor complex. We subsequently assemble viable CD14/TLR4/MD-2 oligomers at the plasma membrane surface, and observe lipopolysaccharide exchange between CD14 and TLR4/MD-2. Collectively, this work helps to unravel the key structural determinants governing endotoxin recognition in the TLR4 innate immune pathway. Huber et al. develop near-atomic computational models to simulate LPS transfer through the TLR4 pathway. These reveal that LPS recognition is favored by a thermodynamic funnel of increasing affinity along a receptor cascade, terminating in productive transfer of LPS at spontaneously assembled CD14/TLR4/MD-2 membrane complexes.

This record has no associated files available for download.

Contributors

Author: Syma Khalid

Download statistics