A transient homotypic interaction model for the influenza A virus NS1 protein effector domain.
Influenza A virus NS1 protein is a multifunctional virulence factor consisting of an RNA binding domain (RBD), a short linker, an effector domain (ED), and a C-terminal 'tail'. Although poorly understood, NS1 multimerization may autoregulate its actions. While RBD dimerization seems functi...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2011-03-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3065461?pdf=render |
| _version_ | 1828848396288393216 |
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| author | Philip S Kerry Juan Ayllon Margaret A Taylor Claudia Hass Andrew Lewis Adolfo García-Sastre Richard E Randall Benjamin G Hale Rupert J Russell |
| author_facet | Philip S Kerry Juan Ayllon Margaret A Taylor Claudia Hass Andrew Lewis Adolfo García-Sastre Richard E Randall Benjamin G Hale Rupert J Russell |
| author_sort | Philip S Kerry |
| collection | DOAJ |
| description | Influenza A virus NS1 protein is a multifunctional virulence factor consisting of an RNA binding domain (RBD), a short linker, an effector domain (ED), and a C-terminal 'tail'. Although poorly understood, NS1 multimerization may autoregulate its actions. While RBD dimerization seems functionally conserved, two possible apo ED dimers have been proposed (helix-helix and strand-strand). Here, we analyze all available RBD, ED, and full-length NS1 structures, including four novel crystal structures obtained using EDs from divergent human and avian viruses, as well as two forms of a monomeric ED mutant. The data reveal the helix-helix interface as the only strictly conserved ED homodimeric contact. Furthermore, a mutant NS1 unable to form the helix-helix dimer is compromised in its ability to bind dsRNA efficiently, implying that ED multimerization influences RBD activity. Our bioinformatical work also suggests that the helix-helix interface is variable and transient, thereby allowing two ED monomers to twist relative to one another and possibly separate. In this regard, we found a mAb that recognizes NS1 via a residue completely buried within the ED helix-helix interface, and which may help highlight potential different conformational populations of NS1 (putatively termed 'helix-closed' and 'helix-open') in virus-infected cells. 'Helix-closed' conformations appear to enhance dsRNA binding, and 'helix-open' conformations allow otherwise inaccessible interactions with host factors. Our data support a new model of NS1 regulation in which the RBD remains dimeric throughout infection, while the ED switches between several quaternary states in order to expand its functional space. Such a concept may be applicable to other small multifunctional proteins. |
| first_indexed | 2024-12-12T22:29:17Z |
| format | Article |
| id | doaj.art-1e53f468b4284a219d9d5eb9b117636c |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-12T22:29:17Z |
| publishDate | 2011-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-1e53f468b4284a219d9d5eb9b117636c2022-12-22T00:09:39ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-03-0163e1794610.1371/journal.pone.0017946A transient homotypic interaction model for the influenza A virus NS1 protein effector domain.Philip S KerryJuan AyllonMargaret A TaylorClaudia HassAndrew LewisAdolfo García-SastreRichard E RandallBenjamin G HaleRupert J RussellInfluenza A virus NS1 protein is a multifunctional virulence factor consisting of an RNA binding domain (RBD), a short linker, an effector domain (ED), and a C-terminal 'tail'. Although poorly understood, NS1 multimerization may autoregulate its actions. While RBD dimerization seems functionally conserved, two possible apo ED dimers have been proposed (helix-helix and strand-strand). Here, we analyze all available RBD, ED, and full-length NS1 structures, including four novel crystal structures obtained using EDs from divergent human and avian viruses, as well as two forms of a monomeric ED mutant. The data reveal the helix-helix interface as the only strictly conserved ED homodimeric contact. Furthermore, a mutant NS1 unable to form the helix-helix dimer is compromised in its ability to bind dsRNA efficiently, implying that ED multimerization influences RBD activity. Our bioinformatical work also suggests that the helix-helix interface is variable and transient, thereby allowing two ED monomers to twist relative to one another and possibly separate. In this regard, we found a mAb that recognizes NS1 via a residue completely buried within the ED helix-helix interface, and which may help highlight potential different conformational populations of NS1 (putatively termed 'helix-closed' and 'helix-open') in virus-infected cells. 'Helix-closed' conformations appear to enhance dsRNA binding, and 'helix-open' conformations allow otherwise inaccessible interactions with host factors. Our data support a new model of NS1 regulation in which the RBD remains dimeric throughout infection, while the ED switches between several quaternary states in order to expand its functional space. Such a concept may be applicable to other small multifunctional proteins.http://europepmc.org/articles/PMC3065461?pdf=render |
| spellingShingle | Philip S Kerry Juan Ayllon Margaret A Taylor Claudia Hass Andrew Lewis Adolfo García-Sastre Richard E Randall Benjamin G Hale Rupert J Russell A transient homotypic interaction model for the influenza A virus NS1 protein effector domain. PLoS ONE |
| title | A transient homotypic interaction model for the influenza A virus NS1 protein effector domain. |
| title_full | A transient homotypic interaction model for the influenza A virus NS1 protein effector domain. |
| title_fullStr | A transient homotypic interaction model for the influenza A virus NS1 protein effector domain. |
| title_full_unstemmed | A transient homotypic interaction model for the influenza A virus NS1 protein effector domain. |
| title_short | A transient homotypic interaction model for the influenza A virus NS1 protein effector domain. |
| title_sort | transient homotypic interaction model for the influenza a virus ns1 protein effector domain |
| url | http://europepmc.org/articles/PMC3065461?pdf=render |
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