title: Variola virus IL-18 binding protein interacts with three human IL-18 residues that are part of a binding site for human IL-18 receptor alpha subunit.
abstract: Interleukin-18 (IL-18) plays an important role in host defense against microbial pathogens. Many poxviruses encode homologous IL-18 binding proteins (IL-18BP) that neutralize IL-18 activity. Here, we examined whether IL-18BP neutralizes IL-18 activity by binding to the same region of IL-18 where IL-18 receptor (IL-18R) binds. We introduced alanine substitutions to known receptor binding sites of human IL-18 and found that only the substitution of Leu5 reduced the binding affinity of IL-18 with IL-18BP of variola virus (varvIL-18BP) by more than 4-fold. The substitutions of Lys53 and Ser55, which were not previously known to be part of the receptor binding site but that are spatially adjacent to Leu5, reduced the binding affinity to varvIL-18BP by approximately 100- and 7-fold, respectively. These two substitutions also reduced the binding affinity with human IL-18R alpha subunit (hIL-18Ralpha) by 4- and 2-fold, respectively. Altogether, our data show that varvIL-18BP prevents IL-18 from binding to IL-18R by interacting with three residues that are part of the binding site for hIL-18Ralpha.
authors.affiliation: Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
authors.forename: Xiangzhi
authors.initials: X
authors.lastname: Meng
authors.forename: Michael
authors.initials: M
authors.lastname: Leman
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiang
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001665:Binding Sites; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D025941:Protein Interaction Mapping; D053724:Receptors, Interleukin-18 / Q000378:metabolism*; D020349:Surface Plasmon Resonance; D012901:Variola virus / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D020382:Interleukin-18; D053724:Receptors, Interleukin-18; D014764:Viral Proteins