A Thermodynamic Funnel Drives Bacterial Lipopolysaccharide Transfer in the TLR4 Pathway

Structure
Roland G HuberPeter J Bond

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.

Citations

Jan 16, 2020·International Journal of Molecular Sciences·Lalita Mazgaeen, Prajwal Gurung
Feb 9, 2020·The Journal of Biological Chemistry·Jitka PetrlovaArtur Schmidtchen
Oct 15, 2019·PLoS Computational Biology·Alireza Tafazzol, Yong Duan
Aug 9, 2020·Frontiers in Immunology·Alessio Romerio, Francesco Peri
Aug 6, 2020·The Journal of Chemical Physics·Jonathan ShearerSyma Khalid
Jul 28, 2019·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Daniel A HoldbrookPeter J Bond
Dec 10, 2020·Journal of Molecular Cell Biology·Ganna PetrukAnd Artur Schmidtchen
Jan 19, 2021·Biophysical Journal·Alejandro Rodríguez GamaRandal Halfmann
Jul 22, 2021·Chemical Reviews·Flaviana Di LorenzoAntonio Molinaro
Jun 7, 2018·Journal of Chemical Theory and Computation·Jan K MarzinekPeter J Bond
Jan 10, 2019·Chemical Reviews·Siewert J MarrinkMark S P Sansom
Jul 2, 2020·Langmuir : the ACS Journal of Surfaces and Colloids·Pradyumn SharmaJaydeep Kumar Basu
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