Title |
Crystal structure of Toll-like receptor adaptor MAL/TIRAP reveals the molecular basis for signal transduction and disease protection
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Published in |
Proceedings of the National Academy of Sciences of the United States of America, August 2011
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DOI | 10.1073/pnas.1104780108 |
Pubmed ID | |
Authors |
Eugene Valkov, Anna Stamp, Frank DiMaio, David Baker, Brett Verstak, Pietro Roversi, Stuart Kellie, Matthew J. Sweet, Ashley Mansell, Nicholas J. Gay, Jennifer L. Martin, Bostjan Kobe |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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Unknown | 1 | 100% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 1 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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United States | 3 | 2% |
Poland | 2 | 2% |
Belgium | 1 | <1% |
France | 1 | <1% |
Japan | 1 | <1% |
United Kingdom | 1 | <1% |
Unknown | 119 | 93% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 31 | 24% |
Researcher | 29 | 23% |
Professor > Associate Professor | 15 | 12% |
Student > Master | 10 | 8% |
Other | 7 | 5% |
Other | 22 | 17% |
Unknown | 14 | 11% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 48 | 38% |
Biochemistry, Genetics and Molecular Biology | 23 | 18% |
Immunology and Microbiology | 9 | 7% |
Medicine and Dentistry | 6 | 5% |
Chemistry | 5 | 4% |
Other | 19 | 15% |
Unknown | 18 | 14% |