Open AccessStructural basis of TIR-domain-assembly formation in MAL- and MyD88-dependent TLR4 signaling
Author(s) -
Thomas Ve,
Parimala R. Vajjhala,
Andrew Hedger,
Tristan I. Croll,
Frank DiMaio,
S. Horsefield,
Yong Xiong,
Peter Lavrencic,
Zurina Hassan,
Garry Morgan,
Ashley Mansell,
Mehdi Mobli,
Ailís O’Carroll,
Brieuc Chauvin,
Yann Gambin,
Emma Sierecki,
Michael J. Landsberg,
Katryn J. Stacey,
Edward H. Egelman,
Boštjan Kobe
Publication year - 2017
Publication title -
nature structural and molecular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.448
H-Index - 270
eISSN - 1545-9993
pISSN - 1545-9985
DOI - 10.1038/nsmb.3444
Subject(s) - innate immune system , microbiology and biotechnology , biology , mutagenesis , receptor , signal transduction , toll like receptor , signal transducing adaptor protein , tlr4 , plasma protein binding , protein structure , mutation , genetics , gene , biochemistry
Toll-like receptor (TLR) signaling is a key innate immunity response to pathogens. Recruitment of signaling adapters such as MAL (TIRAP) and MyD88 to the TLRs requires Toll/interleukin-1 receptor (TIR)-domain interactions, which remain structurally elusive. Here we show that MAL TIR domains spontaneously and reversibly form filaments in vitro. They also form cofilaments with TLR4 TIR domains and induce formation of MyD88 assemblies. A 7-Å-resolution cryo-EM structure reveals a stable MAL protofilament consisting of two parallel strands of TIR-domain subunits in a BB-loop-mediated head-to-tail arrangement. Interface residues that are important for the interaction are conserved among different TIR domains. Although large filaments of TLR4, MAL or MyD88 are unlikely to form during cellular signaling, structure-guided mutagenesis, combined with in vivo interaction assays, demonstrated that the MAL interactions defined within the filament represent a template for a conserved mode of TIR-domain interaction involved in both TLR and interleukin-1 receptor signaling.