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A thermodynamic funnel drives bacterial lipopolysaccharide transfer in the TLR4 pathway

A thermodynamic funnel drives bacterial lipopolysaccharide transfer in the TLR4 pathway
A thermodynamic funnel drives bacterial lipopolysaccharide transfer in the TLR4 pathway

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.

cluster of differentiation 14 (CD14), coarse-grained (CG) models, free-energy calculations, lipopolysaccharide (LPS), molecular dynamics (MD) simulations, myeloid differentiation factor 2 (MD-2), oligomerization, OmpF porin, toll-like receptor 4 (TLR4)
0969-2126
1151-1161
Huber, Roland G.
114d3558-3288-4a57-87cf-c712953a803a
Berglund, Nils A.
01f23146-6b2d-4c6f-a090-85e6dad99ec3
Kargas, Vasileios
4c3b7616-e8a6-4fef-aba7-d9a2e45766d0
Marzinek, Jan K.
64e75d21-98b8-44d8-96f7-5076859e13ec
Holdbrook, Daniel A.
d114c018-fb42-4a49-9b50-f7739feb75f5
Khalid, Syma
90fbd954-7248-4f47-9525-4d6af9636394
Piggot, Thomas J.
75829b71-d73b-43d1-b24f-3e70c2c4d0c8
Schmidtchen, Artur
6e535b6d-0bd1-4664-b854-788eb989c76b
Bond, Peter J.
f6fa881e-cc1e-496c-8811-3433968a9bca
Huber, Roland G.
114d3558-3288-4a57-87cf-c712953a803a
Berglund, Nils A.
01f23146-6b2d-4c6f-a090-85e6dad99ec3
Kargas, Vasileios
4c3b7616-e8a6-4fef-aba7-d9a2e45766d0
Marzinek, Jan K.
64e75d21-98b8-44d8-96f7-5076859e13ec
Holdbrook, Daniel A.
d114c018-fb42-4a49-9b50-f7739feb75f5
Khalid, Syma
90fbd954-7248-4f47-9525-4d6af9636394
Piggot, Thomas J.
75829b71-d73b-43d1-b24f-3e70c2c4d0c8
Schmidtchen, Artur
6e535b6d-0bd1-4664-b854-788eb989c76b
Bond, Peter J.
f6fa881e-cc1e-496c-8811-3433968a9bca

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).

Record type: Article

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.

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More information

Accepted/In Press date: 10 April 2018
e-pub ahead of print date: 17 May 2018
Published date: 7 August 2018
Keywords: cluster of differentiation 14 (CD14), coarse-grained (CG) models, free-energy calculations, lipopolysaccharide (LPS), molecular dynamics (MD) simulations, myeloid differentiation factor 2 (MD-2), oligomerization, OmpF porin, toll-like receptor 4 (TLR4)

Identifiers

Local EPrints ID: 424883
URI: http://eprints.soton.ac.uk/id/eprint/424883
ISSN: 0969-2126
PURE UUID: 3cf03b67-b42f-49fb-af40-7db4d4a4be9b
ORCID for Syma Khalid: ORCID iD orcid.org/0000-0002-3694-5044

Catalogue record

Date deposited: 05 Oct 2018 11:52
Last modified: 15 Sep 2021 01:53

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Contributors

Author: Roland G. Huber
Author: Nils A. Berglund
Author: Vasileios Kargas
Author: Jan K. Marzinek
Author: Daniel A. Holdbrook
Author: Syma Khalid ORCID iD
Author: Thomas J. Piggot
Author: Artur Schmidtchen
Author: Peter J. Bond

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