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  • Structural basis of TIR-domain-assembly formation in MAL- and MyD88-dependent TLR4 signaling

    Author(s)
    Ve, Thomas
    Vajjhala, Parimala R
    Hedger, Andrew
    Croll, Tristan
    DiMaio, Frank
    Horsefield, Shane
    Yu, Xiong
    Lavrencic, Peter
    Hassan, Zahid
    Morgan, Garry P
    Mansell, Ashley
    Mobli, Mehdi
    O'Carroll, Ailis
    Chauvin, Brieuc
    Gambin, Yann
    Sierecki, Emma
    Landsberg, Michael J
    Stacey, Katryn J
    Egelman, Edward H
    Kobe, Bostjan
    Griffith University Author(s)
    Ve, Thomas
    Year published
    2017
    Metadata
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    Abstract
    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 ...
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    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.
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    Journal Title
    Nature Structural and Molecular Biology
    Volume
    24
    DOI
    https://doi.org/10.1038/nsmb.3444
    Subject
    Biochemistry and Cell Biology not elsewhere classified
    Chemical Sciences
    Biological Sciences
    Medical and Health Sciences
    Publication URI
    http://hdl.handle.net/10072/360730
    Collection
    • Journal articles

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