title: Crystal structure of Toll-like receptor adaptor MAL/TIRAP reveals the molecular basis for signal transduction and disease protection.
abstract: Initiation of the innate immune response requires agonist recognition by pathogen-recognition receptors such as the Toll-like receptors (TLRs). Toll/interleukin-1 receptor (TIR) domain-containing adaptors are critical in orchestrating the signal transduction pathways after TLR and interleukin-1 receptor activation. Myeloid differentiation primary response gene 88 (MyD88) adaptor-like (MAL)/TIR domain-containing adaptor protein (TIRAP) is involved in bridging MyD88 to TLR2 and TLR4 in response to bacterial infection. Genetic studies have associated a number of unique single-nucleotide polymorphisms in MAL with protection against invasive microbial infection, but a molecular understanding has been hampered by a lack of structural information. The present study describes the crystal structure of MAL TIR domain. Significant structural differences exist in the overall fold of MAL compared with other TIR domain structures: A sequence motif comprising a β-strand in other TIR domains instead corresponds to a long loop, placing the functionally important "BB loop" proline motif in a unique surface position in MAL. The structure suggests possible dimerization and MyD88-interacting interfaces, and we confirm the key interface residues by coimmunoprecipitation using site-directed mutants. Jointly, our results provide a molecular and structural basis for the role of MAL in TLR signaling and disease protection.
authors.affiliation: School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia. ev269@cam.ac.uk
authors.forename: Eugene
authors.initials: E
authors.lastname: Valkov
authors.forename: Anna
authors.initials: A
authors.lastname: Stamp
authors.forename: Frank
authors.initials: F
authors.lastname: Dimaio
authors.forename: David
authors.initials: D
authors.lastname: Baker
authors.forename: Brett
authors.initials: B
authors.lastname: Verstak
authors.forename: Pietro
authors.initials: P
authors.lastname: Roversi
authors.forename: Stuart
authors.initials: S
authors.lastname: Kellie
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sweet
authors.forename: Ashley
authors.initials: A
authors.lastname: Mansell
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Gay
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Martin
authors.forename: Bostjan
authors.initials: B
authors.lastname: Kobe
mesh_terms: D020816:Amino Acid Motifs; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D007239:Infections; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism; D055503:Protein Multimerization / Q000276:immunology; D017472:Receptors, Interleukin-1 / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013329:Structure-Activity Relationship; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism
chemical_list: C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4