A Thermodynamic Funnel Drives Bacterial Lipopolysaccharide Transfer in the TLR4 Pathway

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A Thermodynamic Funnel Drives Bacterial Lipopolysaccharide Transfer in the TLR4 Pathway
Title:
A Thermodynamic Funnel Drives Bacterial Lipopolysaccharide Transfer in the TLR4 Pathway
Other Titles:
Structure
Publication Date:
17 May 2018
Citation:
Roland G. Huber, Nils A. Berglund, Vasileios Kargas, Jan K. Marzinek, Daniel A. Holdbrook, Syma Khalid, Thomas J. Piggot, Artur Schmidtchen, Peter J. Bond, A Thermodynamic Funnel Drives Bacterial Lipopolysaccharide Transfer in the TLR4 Pathway, Structure, Volume 26, Issue 8, 2018, Pages 1151-1161.e4, ISSN 0969-2126, https://doi.org/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.
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Funding Info:
Description:
The full paper can be downloaded at the publisher's URL: https://doi.org/10.1016/j.str.2018.04.007
ISSN:
0969-2126
1878-4186
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