Structural requirements for the antiviral activity of the human MxA protein against Thogoto and influenza A virus.
The interferon-induced dynamin-like MxA protein has broad antiviral activity against many viruses, including orthomyxoviruses such as influenza A and Thogoto virus and bunyaviruses such as La Crosse virus. MxA consists of an N-terminal globular GTPase domain, a connecting bundle signaling element, and the C-terminal stalk that mediates oligomerization and antiviral specificity. We previously reported that the disordered loop L4 that protrudes from the compact stalk is a key determinant of antiviral specificity against influenza A and Thogoto virus. However, the role of individual amino acids for viral target recognition remained largely undefined. By mutational analyses, we identified two regions in the C-terminal part of L4 that contribute to an antiviral interface. Mutations in the proximal motif, at positions 561 and 562, abolished antiviral activity against orthomyxoviruses but not bunyaviruses. In contrast, mutations in the distal motif, around position 577, abolished antiviral activity against both viruses. These results indicate that at least two structural elements in L4 are responsible for antiviral activity and that the proximal motif determines specificity for orthomyxoviruses, whereas the distal sequence serves a conserved structural function.
From the Institute of Virology, University of Freiburg, 79008 Freiburg, Germany.
Corinna
C
Patzina
Otto
O
Haller
Georg
G
Kochs
D020816:Amino Acid Motifs; D000818:Animals; D002522:Chlorocebus aethiops; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype; D007251:Influenza, Human; D009154:Mutation; D064547:Myxovirus Resistance Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D018117:Thogotovirus
C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins
Antiviral Agents; Dynamin; GTPase; Influenza Virus; Innate Immunity; Interferon; MxA; Myxovirus Resistance