2026-07-18T17:05:06Zhttps://riubu.ubu.es/oai/request

oai:riubu.ubu.es:10259/79972023-11-23T12:25:34Zcom_10259_4862com_10259_5086com_10259_2604col_10259_4863

Kerry, Philip S. Ayllón Barasoain, Juan Taylor, Margaret A. Hass, Claudia Lewis, Andrew García Sastre, Adolfo Randall, Richard E. Hale, Benjamin G. Russell, Rupert J. 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. 2023-11-13 2023-11-13 2011 info:eu-repo/semantics/article http://hdl.handle.net/10259/7997 10.1371/journal.pone.0017946 1932-6203 eng PLoS ONE. 2011, V. 6, n. 3, e17946 https://doi.org/10.1371/journal.pone.0017946 http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess Atribución 4.0 Internacional Public Library of Science