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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Dufner, Matthew Donovan, Jesse Korennykh, Alexei |
| Description | Author Affiliation: Donovan J ( Department of Molecular Biology, Princeton University, Princeton, NJ 08540, USA.); |
| Abstract | The human sensor of double-stranded RNA (dsRNA) oligoadenylate synthetase 1 (hOAS1) polymerizes ATP into 2′,5′-linked iso-RNA (2-5A) involved in innate immunity, cell cycle, and differentiation. We report the crystal structure of hOAS1 in complex with dsRNA and 2′-deoxy ATP at 2.7 Å resolution, which reveals the mechanism of cytoplasmic dsRNA recognition and activation of oligoadenylate synthetases. Human OAS1 recognizes dsRNA using a previously uncharacterized protein/RNA interface that forms via a conformational change induced by binding of dsRNA. The protein/RNA interface involves two minor grooves and has no sequence-specific contacts, with the exception of a single hydrogen bond between the $-NH_{2}$ group of nucleobase G17 and the carbonyl oxygen of serine 56. Using a biochemical readout, we show that hOAS1 undergoes more than 20,000-fold activation upon dsRNA binding and that canonical or GU-wobble substitutions produce dsRNA mutants that retain either full or partial activity, in agreement with the crystal structure. Ultimately, the binding of dsRNA promotes an elaborate conformational rearrangement in the N-terminal lobe of hOAS1, which brings residues D75, D77, and D148 into proximity and creates coordination geometry for binding of two catalytic $Mg^{2+}$ ions and ATP. The assembly of this critical active-site structure provides the gate that couples binding of dsRNA to the production and downstream functions of 2-5A. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 5 |
| Volume Number | 110 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2013-01-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | 2',5'-Oligoadenylate Synthetase Chemistry Nucleic Acid Conformation Protein Structure, Tertiary RNA, Double-Stranded Metabolism Adenine Nucleotides Amino Acid Sequence Binding Sites Genetics Biocatalysis Crystallography, X-Ray Cytosol Deoxyadenine Nucleotides Enzyme Activation Models, Molecular Molecular Sequence Data Oligoribonucleotides Protein Binding Sequence Homology, Amino Acid Substrate Specificity Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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