Proceedings of the National Academy of Sciences - PNAS, 2011-09, Vol.108 (36), p.14879-14884
2011
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- Autor(en) / Beteiligte
- Titel
- Crystal structure of Toll-like receptor adaptor MAL/TIRAP reveals the molecular basis for signal transduction and disease protection
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2011-09, Vol.108 (36), p.14879-14884
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2011
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.1104780108Titel-ID: cdi_pnas_primary_108_36_14879
- Format
- –
- Schlagworte
- adaptor proteins, agonists, Amino Acid Motifs, Biological Sciences, Crystal structure, Differentiation, Dimerization, Dimers, genes, Humans, Immune response, immunity, Immunity, Innate - physiology, Infection, Infections, Innate immunity, Interleukin 1, Membrane Glycoproteins - chemistry, Membrane Glycoproteins - immunology, Membrane Glycoproteins - metabolism, Molecular structure, Molecules, mutants, Mutation, MyD88 protein, Myeloid Differentiation Factor 88 - immunology, Myeloid Differentiation Factor 88 - metabolism, Phosphorylation, Polymorphism, Proline, Protein Multimerization - immunology, Receptor mechanisms, Receptors, Receptors, Interleukin-1 - chemistry, Receptors, Interleukin-1 - immunology, Receptors, Interleukin-1 - metabolism, Signal transduction, Signal Transduction - physiology, Single-nucleotide polymorphism, Structure-Activity Relationship, T cell receptors, TLR2 protein, TLR4 protein, Toll like receptors, Toll-Like Receptor 2 - immunology, Toll-Like Receptor 2 - metabolism, Toll-Like Receptor 4 - immunology, Toll-Like Receptor 4 - metabolism