Plus Significance Statements Solution structure of the TLR adaptor MAL / TIRAP reveals an intact BB loop and supports MAL Cys 91 glutathionylation for signaling

Toll-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. (See pp. E6480–E6489.)