Structural and Functional Analysis of DDX41: a bispecific immune receptor for DNA and cyclic dinucleotide
| Autor: | Osamu Nureki, Fuminori Tokunaga, Megumi Kato, Hiroki Omura, Daisuke Oikawa, Takanori Nakane, Ryuichiro Ishitani, Ryohei Ishii |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Models Molecular DEAD box Protein Conformation Immune receptor Plasma protein binding Biology Crystallography X-Ray Article DEAD-box RNA Helicases 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Adenosine Triphosphate Humans Binding site Transcription factor Multidisciplinary Binding Sites Pattern recognition receptor Membrane Proteins DNA Immunity Innate Cell biology 030104 developmental biology Biochemistry chemistry 030220 oncology & carcinogenesis Signal transduction Nucleotides Cyclic Adenosine triphosphate Protein Binding Signal Transduction |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep34756 |
| Popis: | In the innate immune system, pattern recognition receptors (PRRs) specifically recognize ligands derived from bacteria or viruses, to trigger the responsible downstream pathways. DEAD box protein 41 (DDX41) is an intracellular PRR that triggers the downstream pathway involving the adapter STING, the kinase TBK1, and the transcription factor IRF3, to activate the type I interferon response. DDX41 is unique in that it recognizes two different ligands; i.e., double-stranded DNA (dsDNA) and cyclic dinucleotides (CDN), via its DEAD domain. However, the structural basis for the ligand recognition by the DDX41 DEAD domain has remained elusive. Here, we report two crystal structures of the DDX41 DEAD domain in apo forms, at 1.5 and 2.2 Å resolutions. A comparison of the two crystal structures revealed the flexibility in the ATP binding site, suggesting its formation upon ATP binding. Structure-guided functional analyses in vitro and in vivo demonstrated the overlapped binding surface for dsDNA and CDN, which is distinct from the ATP-binding site. We propose that the structural rearrangement of the ATP binding site is crucial for the release of ADP, enabling the fast turnover of DDX41 for the dsDNA/CDN-induced STING activation pathway. |
| Databáze: | OpenAIRE |
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