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

Research output: Contribution to journalArticle

19 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 languageEnglish
Pages (from-to)E6480-E6489
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number32
Early online date24 Jul 2017
DOIs
Publication statusPublished - 08 Aug 2017

Keywords

  • Glutathione
  • Inflammation
  • MAL/TIRAP
  • NMR spectrometry
  • Toll-like receptor

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Solution structure of the TLR adaptor MAL/TIRAP reveals an intact BB loop and supports MAL Cys91 glutathionylation for signaling'. Together they form a unique fingerprint.

Cite this