Structure and mechanism of IFN-gamma antagonism by an orthopoxvirus IFN-gamma-binding protein.
Ectromelia virus (ECTV) encodes an IFN-gamma-binding protein (IFN-gammaBP(ECTV)) that disrupts IFN-gamma signaling and its ability to induce an antiviral state within cells. IFN-gammaBP(ECTV) is an important virulence factor that is highly conserved (>90%) in all orthopoxviruses, including variola virus, the causative agent of smallpox. The 2.2-A crystal structure of the IFN-gammaBP(ECTV)/IFN-gamma complex reveals IFN-gammaBP(ECTV) consists of an IFN-gammaR1 ligand-binding domain and a 57-aa helix-turn-helix (HTH) motif that is structurally related to the transcription factor TFIIA. The HTH motif forms a tetramerization domain that results in an IFN-gammaBP(ECTV)/IFN-gamma complex containing four IFN-gammaBP(ECTV) chains and two IFN-gamma dimers. The structure, combined with biochemical and cell-based assays, demonstrates that IFN-gammaBP(ECTV) tetramers are required for efficient IFN-gamma antagonism.
Nuara
Anthony A
AA
Center for Biophysical Sciences and Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Walter
Leigh J
LJ
Logsdon
Naomi J
NJ
Yoon
Sung Il
SI
Jones
Brandi C
BC
Schriewer
Jill M
JM
Buller
R Mark
RM
Walter
Mark R
MR
D000818:Animals; D002846:Chromatography, Affinity; D006860:Hydrogen Bonding; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D018155:Orthopoxvirus / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D014764:Viral Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*
D014764:Viral Proteins; D007371:Interferon-gamma