Molecular Basis of the Ternary Interaction between NS1 of the 1918 Influenza A Virus, PI3K, and CRK
The 1918 influenza A virus (IAV) caused the worst flu pandemic in human history. Non-structural protein 1 (NS1) is an important virulence factor of the 1918 IAV and antagonizes host antiviral immune responses. NS1 increases virulence by activating phosphoinositide 3-kinase (PI3K) via binding to the...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-03-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/12/3/338 |
| _version_ | 1818934486083043328 |
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| author | Alyssa Dubrow Sirong Lin Nowlan Savage Qingliang Shen Jae-Hyun Cho |
| author_facet | Alyssa Dubrow Sirong Lin Nowlan Savage Qingliang Shen Jae-Hyun Cho |
| author_sort | Alyssa Dubrow |
| collection | DOAJ |
| description | The 1918 influenza A virus (IAV) caused the worst flu pandemic in human history. Non-structural protein 1 (NS1) is an important virulence factor of the 1918 IAV and antagonizes host antiviral immune responses. NS1 increases virulence by activating phosphoinositide 3-kinase (PI3K) via binding to the p85β subunit of PI3K. Intriguingly, unlike the NS1 of other human IAV strains, 1918 NS1 hijacks another host protein, CRK, to form a ternary complex with p85β, resulting in hyperactivation of PI3K. However, the molecular basis of the ternary interaction between 1918 NS1, CRK, and PI3K remains elusive. Here, we report the structural and thermodynamic bases of the ternary interaction. We find that the C-terminal tail (CTT) of 1918 NS1 remains highly flexible in the complex with p85β. Thus, the CTT of 1918 NS1 in the complex with PI3K can efficiently hijack CRK. Notably, our study indicates that 1918 NS1 enhances its affinity to p85β in the presence of CRK, which might result in enhanced activation of PI3K. Our results provide structural insight into how 1918 NS1 hijacks two host proteins simultaneously. |
| first_indexed | 2024-12-20T05:05:02Z |
| format | Article |
| id | doaj.art-d41aca4503da4207bd9db81ef7c2ba10 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-12-20T05:05:02Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-d41aca4503da4207bd9db81ef7c2ba102022-12-21T19:52:25ZengMDPI AGViruses1999-49152020-03-0112333810.3390/v12030338v12030338Molecular Basis of the Ternary Interaction between NS1 of the 1918 Influenza A Virus, PI3K, and CRKAlyssa Dubrow0Sirong Lin1Nowlan Savage2Qingliang Shen3Jae-Hyun Cho4Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USADepartment of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USADepartment of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USADepartment of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USADepartment of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USAThe 1918 influenza A virus (IAV) caused the worst flu pandemic in human history. Non-structural protein 1 (NS1) is an important virulence factor of the 1918 IAV and antagonizes host antiviral immune responses. NS1 increases virulence by activating phosphoinositide 3-kinase (PI3K) via binding to the p85β subunit of PI3K. Intriguingly, unlike the NS1 of other human IAV strains, 1918 NS1 hijacks another host protein, CRK, to form a ternary complex with p85β, resulting in hyperactivation of PI3K. However, the molecular basis of the ternary interaction between 1918 NS1, CRK, and PI3K remains elusive. Here, we report the structural and thermodynamic bases of the ternary interaction. We find that the C-terminal tail (CTT) of 1918 NS1 remains highly flexible in the complex with p85β. Thus, the CTT of 1918 NS1 in the complex with PI3K can efficiently hijack CRK. Notably, our study indicates that 1918 NS1 enhances its affinity to p85β in the presence of CRK, which might result in enhanced activation of PI3K. Our results provide structural insight into how 1918 NS1 hijacks two host proteins simultaneously.https://www.mdpi.com/1999-4915/12/3/3381918 influenza a virusnonstructural protein 1crkpi3kternary interaction |
| spellingShingle | Alyssa Dubrow Sirong Lin Nowlan Savage Qingliang Shen Jae-Hyun Cho Molecular Basis of the Ternary Interaction between NS1 of the 1918 Influenza A Virus, PI3K, and CRK Viruses 1918 influenza a virus nonstructural protein 1 crk pi3k ternary interaction |
| title | Molecular Basis of the Ternary Interaction between NS1 of the 1918 Influenza A Virus, PI3K, and CRK |
| title_full | Molecular Basis of the Ternary Interaction between NS1 of the 1918 Influenza A Virus, PI3K, and CRK |
| title_fullStr | Molecular Basis of the Ternary Interaction between NS1 of the 1918 Influenza A Virus, PI3K, and CRK |
| title_full_unstemmed | Molecular Basis of the Ternary Interaction between NS1 of the 1918 Influenza A Virus, PI3K, and CRK |
| title_short | Molecular Basis of the Ternary Interaction between NS1 of the 1918 Influenza A Virus, PI3K, and CRK |
| title_sort | molecular basis of the ternary interaction between ns1 of the 1918 influenza a virus pi3k and crk |
| topic | 1918 influenza a virus nonstructural protein 1 crk pi3k ternary interaction |
| url | https://www.mdpi.com/1999-4915/12/3/338 |
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