2026-06-29T18:19:47Zhttps://riubu.ubu.es/oai/request

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

A Transient Homotypic Interaction Model for the Influenza A Virus NS1 Protein Effector Domain 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. 2023-11-13T08:06:30Z 2023-11-13T08:06:30Z 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