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dc.contributor.authorVe, Thomas
dc.contributor.authorVajjhala, Parimala R
dc.contributor.authorHedger, Andrew
dc.contributor.authorCroll, Tristan
dc.contributor.authorDiMaio, Frank
dc.contributor.authorHorsefield, Shane
dc.contributor.authorYu, Xiong
dc.contributor.authorLavrencic, Peter
dc.contributor.authorHassan, Zahid
dc.contributor.authorMorgan, Garry P
dc.contributor.authorMansell, Ashley
dc.contributor.authorMobli, Mehdi
dc.contributor.authorO'Carroll, Ailis
dc.contributor.authorChauvin, Brieuc
dc.contributor.authorGambin, Yann
dc.contributor.authorSierecki, Emma
dc.contributor.authorLandsberg, Michael J
dc.contributor.authorStacey, Katryn J
dc.contributor.authorEgelman, Edward H
dc.contributor.authorKobe, Bostjan
dc.description.abstractToll-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.
dc.publisherNature Publishing Group
dc.relation.ispartofjournalNature Structural and Molecular Biology
dc.subject.fieldofresearchBiochemistry and Cell Biology not elsewhere classified
dc.subject.fieldofresearchMedical and Health Sciences
dc.subject.fieldofresearchChemical Sciences
dc.subject.fieldofresearchBiological Sciences
dc.titleStructural basis of TIR-domain-assembly formation in MAL- and MyD88-dependent TLR4 signaling
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.facultyOffice of the Snr Dep Vice Chancellor, Institute for Glycomics
gro.hasfulltextNo Full Text
gro.griffith.authorVe, Thomas

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