title: Evolution-guided identification of antiviral specificity determinants in the broadly acting interferon-induced innate immunity factor MxA.
abstract: MxA is an interferon-induced dynamin-like GTPase with wide-ranging antiviral activity, which hinges upon detection of unique viral structures that differ across virus families. Despite elucidation of its structure, the basis of MxA antiviral specificity remains enigmatic. We used an evolution-guided approach to identify the loop L4 of MxA as a hotspot for recurrent positive selection in primates. Further, we show that single amino acid changes in L4 are necessary and sufficient to explain dramatic differences in species-specific antiviral activity of primate MxA proteins against the orthomyxoviruses Thogoto virus and influenza A virus. Taken together, our findings identify a genetic determinant of MxA target recognition and suggest a model by which MxA achieves antiviral breadth without compromising viral specificity.
authors.affiliation: Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98185, USA.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Mitchell
authors.forename: Corinna
authors.initials: C
authors.lastname: Patzina
authors.forename: Michael
authors.initials: M
authors.lastname: Emerman
authors.forename: Otto
authors.initials: O
authors.lastname: Haller
authors.forename: Harmit S
authors.initials: HS
authors.lastname: Malik
authors.forename: Georg
authors.initials: G
authors.lastname: Kochs
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019143:Evolution, Molecular; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D009980:Influenza A virus / Q000276:immunology; D008969:Molecular Sequence Data; D064547:Myxovirus Resistance Proteins; D010802:Phylogeny; D011323:Primates; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D018117:Thogotovirus / Q000276:immunology
chemical_list: C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D019204:GTP-Binding Proteins