Structure and Sequence Determinants Governing the Interactions of RNAs with Influenza A Virus Non-Structural Protein NS1
Abstract
:1. Introduction
2. Materials and Methods
2.1. Rescue of Recombinant Influenza Viruses
2.2. Cells, Infections, Virus Titration, and Multicycle Growth Kinetics
2.3. Immunodetection of NS1 and NP
2.4. Minigenome Assay
2.5. RNA Probes and Proteins
2.6. Electrophoretic Mobility Shift Assays (EMSA)
2.7. X-ray 3D Structure Determination
3. Results
3.1. Biological Relevance of the UGAUUGAAG Motif
3.2. Functional and/or Structural Insights into the NS1-RNA Interactions
3.2.1. Minimal Structure of Selected Aptamers for Efficient Recognition by NS1
3.2.2. Major Contribution of the RBD in the Recognition of DM01-Midi and DM03-Midi
3.2.3. Contribution of the AGCAAAAG and GUAAC Motifs to the Interaction
3.2.4. AWFC01, a High-Affinity dsRNA Containing Two GUAAC Motifs
3.3. Structural Basis of NS1′s Interaction with Model dsRNA AWFC01
4. Discussion
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Name | nt Sequence / 2D Structure | Length (nt) | RBD Binding | Reference |
---|---|---|---|---|
DM01 | | 81 | ++++ | [13] |
DM01-midi | | 50 | ++++ | this work |
DM01-short | | 30 | + / - - - | this work |
DM01-mot A | | 8 | - | this work |
DM03 | | 81 | ++++ | [13] |
DM03-midi | | 50 | ++++ | this work |
DM03-short | | 32 | + / - - - | this work |
DM03-mot B | | 9 | - | this work |
RBD. | KD (nM) |
---|---|
H7N1 | 0.83 ± 0.03 |
H7N1 R38A-K41A | NA (>50 µM) |
H5N1 | 0.98 ± 0.04 |
H5N1 R38A-K41A | NA (>100) |
H7N9 | 3.1 ± 0.1 |
H3N2 | 3.7 ± 0.1 |
H17N10 | 1.5 ± 0.1 |
pdmH1N1 | 2.05 ± 0.02 |
RNA Competitor | EC50app (nM) | ||
---|---|---|---|
2D-structure | Name | H5N1 | H7N1 |
| AWFC01 | 1.0 ± 0.1 | 1.7 ± 0.1 |
| DM01-midi | 2.2 ± 0.2 | 2.7 ± 0.1 |
| DM03-midi | 1.8 ± 0.1 | 2.8 ± 0.1 |
| shDM02-GAGA | 0.41 ± 0.02 | 0.24 ± 0.01 |
| shDM03-GAGA | 1.2 ± 0.1 | 0.64 ± 0.06 |
| shDM05-GAGA | 100 ± 11 | ND |
| shDM06-GAGA | 1.1 ± 0.1 | 0.85 ± 0.05 |
| ZKO-RNA | 90 ± 4 | 96 ± 3 |
wt-RBD / AWFC01 | aa-RBD / AWFC01 | wt-RBD / ZKO * | 2ZKO | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
RBD chain A | RBD chain B | RBD chain A | RBD chain B | RBD chain A | RBD chain B | RBD chain A | RBD chain B | |||||||||
Atom 1 | dist. | Atom 2 | dist. | Atom 2 | dist. | Atom 2 | dist. | Atom 2 | dist. | Atom 2 | dist. | Atom 2 | dist. | Atom 2 | dist. | Atom 2 |
Amino-acid / phosphate H-bonds | ||||||||||||||||
H(-1) N | 3.37 | U19(C)OP1 | ||||||||||||||
R38 N(ε) | 2.92 (b) | C6(D)OP1 | 2.76 | C6(C)OP1 | 3.18 | G6(D)OP1 | 2.98 | G6(C)OP1 | 3.47 | G6(D)OP1 | 3.42 | G6(C)OP1 | ||||
R38 N(η1) | 3.23 (b) | C6(D)OP1 | ||||||||||||||
R38 N(η1) | 2.99 (b) | U7(D)OP2 | 2.88 | U7(D)OP1 | 2.59 | C7(C)OP1 | 2.77 | C7(D)OP1 | 2.76 | C7(C)OP1 | 2.76 | C7(D)OP1 | ||||
R38 N(η2) | 3.26 | C6(C)OP1 | 3.18 | G6(D)OP1 | 3.16 | G6(C)OP1 | 3.43 | G6(D)OP1 | 3.35 | G6(C)OP1 | ||||||
R38 N(η2) | 2.32 (a) 2.27 (b) | U7(C)OP1 | 3.06 | U7(C)OP2 | 2.96 | C7(D)OP2 | 2.77 | C7(C)OP2 | 2.83 | C7(D)OP2 | 2.87 | C7(C)OP2 | ||||
S42 O(γ) | 2.87 | A5(D)O3’ | 2.91 | A5(C)O3’ | ||||||||||||
Amino-acid / ribose H-bonds | ||||||||||||||||
S1 O(γ) | 2.49 | U17(C)O2’ | ||||||||||||||
P31 O | 3.71 | C6(C)O2’ | 3.61 | C6(D)O2’ | 3.59 | C6(C)O2’ | 3.54 | C6(D)O2’ | 3.63 | G6(C)O2’ | 3.69 | G6(D)O2’ | 3.67 | G6(D)O2’ | ||
R35 N(η1) | 3.54 | C6(C)O2’ | 3.66 | C6(D)O2’ | 3.55 | C6(C)O2’ | 3.51 | C6(D)O2’ | 3.44 | G6(C)O2’ | 3.38 | G6(D)O2’ | 3.14 | G6(C)O2’ | 3.22 | G6(D)O2’ |
R37 N(η) | 3.43 (a) | U7(D)O2’ | ||||||||||||||
T49 O(γ) | 3.19 | A4(D)O2’ | 3.17 | A4(C)O2’ | 3.00 | A4(D)O2’ | 3.11 | A4(C)O2’ | 2.81 | C4(D)O2’ | 3.10 | C4(C)O2’ | 2.82 | C4(D)O2’ | 2.80 | C4(C)O2’ |
T49 O(γ) | 3.01 | A4(D)O4’ | 3.06 | A4(C)O4’ | 3.08 | A4(D)O4’ | 2.96 | A4(C)O4’ | 2.99 | C4(D)O4’ | 2.94 | C4(C)O4’ | 3.03 | C4(D)O4’ | 3.03 | C4(C)O4’ |
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Wacquiez, A.; Coste, F.; Kut, E.; Gaudon, V.; Trapp, S.; Castaing, B.; Marc, D. Structure and Sequence Determinants Governing the Interactions of RNAs with Influenza A Virus Non-Structural Protein NS1. Viruses 2020, 12, 947. https://doi.org/10.3390/v12090947
Wacquiez A, Coste F, Kut E, Gaudon V, Trapp S, Castaing B, Marc D. Structure and Sequence Determinants Governing the Interactions of RNAs with Influenza A Virus Non-Structural Protein NS1. Viruses. 2020; 12(9):947. https://doi.org/10.3390/v12090947
Chicago/Turabian StyleWacquiez, Alan, Franck Coste, Emmanuel Kut, Virginie Gaudon, Sascha Trapp, Bertrand Castaing, and Daniel Marc. 2020. "Structure and Sequence Determinants Governing the Interactions of RNAs with Influenza A Virus Non-Structural Protein NS1" Viruses 12, no. 9: 947. https://doi.org/10.3390/v12090947