Solution structure of the TLR adaptor MAL/TIRAP reveals an intact BB loop and supports MAL Cys91 glutathionylation for signaling

Mark M. Hughes; Peter Lavrencic; Rebecca C. Coll; Thomas Ve; Dylan G. Ryan; Niamh C. Williams; Deepthi Menon; Ashley Mansell; Philip G. Board; Mehdi Mobli; Bostjan Kobe; Luke A.J. O’Neill

doi:10.1073/pnas.1701868114

Solution structure of the TLR adaptor MAL/TIRAP reveals an intact BB loop and supports MAL Cys91 glutathionylation for signaling

Mark M. Hughes, Peter Lavrencic, Rebecca C. Coll, Thomas Ve, Dylan G. Ryan, Niamh C. Williams, Deepthi Menon, Ashley Mansell, Philip G. Board, Mehdi Mobli^*, Bostjan Kobe, Luke A.J. O’Neill

^*Corresponding author for this work

School of Medicine, Dentistry and Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

31 Citations (Scopus)

Abstract

oll-like receptor (TLR) signaling pathways are targeted to limit inflammation in immune cells. TLRs use adaptor proteins to drive inflammatory signaling platforms for effective microbial clearance. Here we show that MyD88 adaptor-like (MAL), an adaptor protein in TLR signaling, undergoes glutathionylation in response to LPS, driving macrophage responses to proinflammatory stimuli. We also determined the solution structure of MAL in the reduced form without disulfides, revealing a typical BB loop observed in adaptor proteins, in contrast to previously reported crystal structures. This alternate solution structure reveals the inherent flexibility of MAL, supporting the hypothesis that glutathionylation may reposition the MAL BB loop for MyD88 interaction to drive inflammation. This discovery could lead to novel approaches to target MAL glutathionylation in dysregulated TLR signaling, limiting inflammation.

Original language	English
Pages (from-to)	E6480-E6489
Number of pages	10
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	114
Issue number	32
Early online date	24 Jul 2017
DOIs	https://doi.org/10.1073/pnas.1701868114
Publication status	Published - 08 Aug 2017

Keywords

Glutathione
Inflammation
MAL/TIRAP
NMR spectrometry
Toll-like receptor

ASJC Scopus subject areas

General

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10.1073/pnas.1701868114

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Hughes, M. M., Lavrencic, P., Coll, R. C., Ve, T., Ryan, D. G., Williams, N. C., Menon, D., Mansell, A., Board, P. G., Mobli, M., Kobe, B., & O’Neill, L. A. J. (2017). Solution structure of the TLR adaptor MAL/TIRAP reveals an intact BB loop and supports MAL Cys91 glutathionylation for signaling. Proceedings of the National Academy of Sciences of the United States of America, 114(32), E6480-E6489. https://doi.org/10.1073/pnas.1701868114

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title = "Solution structure of the TLR adaptor MAL/TIRAP reveals an intact BB loop and supports MAL Cys91 glutathionylation for signaling",

abstract = "oll-like receptor (TLR) signaling pathways are targeted to limit inflammation in immune cells. TLRs use adaptor proteins to drive inflammatory signaling platforms for effective microbial clearance. Here we show that MyD88 adaptor-like (MAL), an adaptor protein in TLR signaling, undergoes glutathionylation in response to LPS, driving macrophage responses to proinflammatory stimuli. We also determined the solution structure of MAL in the reduced form without disulfides, revealing a typical BB loop observed in adaptor proteins, in contrast to previously reported crystal structures. This alternate solution structure reveals the inherent flexibility of MAL, supporting the hypothesis that glutathionylation may reposition the MAL BB loop for MyD88 interaction to drive inflammation. This discovery could lead to novel approaches to target MAL glutathionylation in dysregulated TLR signaling, limiting inflammation.",

keywords = "Glutathione, Inflammation, MAL/TIRAP, NMR spectrometry, Toll-like receptor",

author = "Hughes, {Mark M.} and Peter Lavrencic and Coll, {Rebecca C.} and Thomas Ve and Ryan, {Dylan G.} and Williams, {Niamh C.} and Deepthi Menon and Ashley Mansell and Board, {Philip G.} and Mehdi Mobli and Bostjan Kobe and O{\textquoteright}Neill, {Luke A.J.}",

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month = aug,

day = "8",

doi = "10.1073/pnas.1701868114",

language = "English",

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Hughes, MM, Lavrencic, P, Coll, RC, Ve, T, Ryan, DG, Williams, NC, Menon, D, Mansell, A, Board, PG, Mobli, M, Kobe, B & O’Neill, LAJ 2017, 'Solution structure of the TLR adaptor MAL/TIRAP reveals an intact BB loop and supports MAL Cys91 glutathionylation for signaling', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 32, pp. E6480-E6489. https://doi.org/10.1073/pnas.1701868114

Solution structure of the TLR adaptor MAL/TIRAP reveals an intact BB loop and supports MAL Cys91 glutathionylation for signaling. / Hughes, Mark M.; Lavrencic, Peter; Coll, Rebecca C. et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 32, 08.08.2017, p. E6480-E6489.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Solution structure of the TLR adaptor MAL/TIRAP reveals an intact BB loop and supports MAL Cys91 glutathionylation for signaling

AU - Hughes, Mark M.

AU - Lavrencic, Peter

AU - Coll, Rebecca C.

AU - Ve, Thomas

AU - Ryan, Dylan G.

AU - Williams, Niamh C.

AU - Menon, Deepthi

AU - Mansell, Ashley

AU - Board, Philip G.

AU - Mobli, Mehdi

AU - Kobe, Bostjan

AU - O’Neill, Luke A.J.

PY - 2017/8/8

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AB - oll-like receptor (TLR) signaling pathways are targeted to limit inflammation in immune cells. TLRs use adaptor proteins to drive inflammatory signaling platforms for effective microbial clearance. Here we show that MyD88 adaptor-like (MAL), an adaptor protein in TLR signaling, undergoes glutathionylation in response to LPS, driving macrophage responses to proinflammatory stimuli. We also determined the solution structure of MAL in the reduced form without disulfides, revealing a typical BB loop observed in adaptor proteins, in contrast to previously reported crystal structures. This alternate solution structure reveals the inherent flexibility of MAL, supporting the hypothesis that glutathionylation may reposition the MAL BB loop for MyD88 interaction to drive inflammation. This discovery could lead to novel approaches to target MAL glutathionylation in dysregulated TLR signaling, limiting inflammation.

KW - Glutathione

KW - Inflammation

KW - MAL/TIRAP

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KW - Toll-like receptor

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JF - Proceedings of the National Academy of Sciences of the United States of America

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ER -

Solution structure of the TLR adaptor MAL/TIRAP reveals an intact BB loop and supports MAL Cys91 glutathionylation for signaling

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