2026-05-24T01:30:17Zhttps://riubu.ubu.es/oai/requestoai:riubu.ubu.es:10259/79972023-11-23T12:25:34Zcom_10259_4862com_10259_5086com_10259_2604col_10259_4863
Kerry, Philip S.
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Ayllón Barasoain, Juan
852
600
0000-0002-7556-8106
Taylor, Margaret A.
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Hass, Claudia
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Lewis, Andrew
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García Sastre, Adolfo
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600
Randall, Richard E.
ccfee2e2-0995-43d6-846b-4d057f160591
Hale, Benjamin G.
acc3bd63-b78d-4900-a8fb-06b2d01623cf
Russell, Rupert J.
c7af9378-a8d5-4b5b-a64b-b7b7da8fde3c
2023-11-13T08:06:30Z
2023-11-13T08:06:30Z
2011
http://hdl.handle.net/10259/7997
10.1371/journal.pone.0017946
1932-6203
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.
Work in St. Andrews was supported by the Medical Research Council, UK (RER and RJR), and the Scottish Funding Council (RJR). Work performed at MSSM was partially supported by CRIP, a National Institute of Allergy and Infectious Diseases (NIAID) funded Center for Research in Influenza Pathogenesis (contract number HHSN266200700010C), and by NIAID grants RO1AI46954, U19AI83025 and PO1AI58113 (to AG-S). Confocal laser scanning microscopy was performed at the MSSM-Microscopy Shared Resource Facility, supported with funding from National Institutes of Health-National Cancer Institute (NIH-NCI) shared resources grant (5R24 CA095823-04), NSF Major Research Instrumentation grant (DBI-9724504) and NIH shared instrumentation grant (1 S10 RR0 9145-01). The University of St. Andrews is a charity registered in Scotland (No. SC013532). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
application/pdf
eng
Public Library of Science
PLoS ONE. 2011, V. 6, n. 3, e17946
https://doi.org/10.1371/journal.pone.0017946
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
Medicina
Salud
Microbiología
Enfermedades infecciosas
Medicine
Health
Microbiology
Communicable diseases
A Transient Homotypic Interaction Model for the Influenza A Virus NS1 Protein Effector Domain
info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
PLoS ONE
6
3
e17946
THUMBNAIL
Kerry-PlosOne_2011.pdf.jpg
Kerry-PlosOne_2011.pdf.jpg
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https://riubu.ubu.es/bitstream/10259/7997/3/license.txt
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ORIGINAL
Kerry-PlosOne_2011.pdf
Kerry-PlosOne_2011.pdf
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10259/7997
oai:riubu.ubu.es:10259/7997
2023-11-23 13:25:34.088
Repositorio Institucional de la Universidad de Burgos
bubrep@ubu.es
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