Correspondence of the Functional Epitopes of Poxvirus and Human Interleukin-18-Binding Proteins
- 15 October 2001
- journal article
- research article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 75 (20), 9947-9954
- https://doi.org/10.1128/jvi.75.20.9947-9954.2001
Abstract
Molluscum contagiosum virus, a human poxvirus that causes persistent small benign skin tumors, encodes a variety of putative immune defense proteins. Three such proteins, MC51L, MC53L, and MC54L, have 20 to 35% amino acid sequence identities with human interleukin-18 (hIL-18)-binding protein (hIL-18BP), a naturally occurring antagonist of the proinflammatory cytokine IL-18. We previously demonstrated that seven amino acids within the immunoglobulin-like domain of hIL-18BP were important for high-affinity binding to hIL-18. Model building indicated that MC54L, which has been shown to bind hIL-18, contains five of the seven amino acids at corresponding positions in its immunoglobulin-like domain, the exceptions being the conservative substitution of isoleucine for a leucine and the nonconservative substitution of valine for a phenylalanine. We found that individual alanine substitutions for these six identical or highly conserved amino acids of MC54L caused changes in affinity and binding free energy for hIL-18 that were quantitatively similar to those produced by mutagenesis of hIL-18BP. Furthermore, when the nonconserved valine of MC54L was mutated to phenylalanine, making it more like hIL-18BP, its affinity for hIL-18 increased more than 10-fold. In addition, the carboxyl-terminal half of MC54L, which has no similarity with hIL-18BP, was dispensable for hIL-18 binding. Thus, despite their relatively low overall sequence identity, MC54L and hIL-18BP have similar hIL-18 binding sites and functional epitopes. On the other hand, MC51L and MC53L have nonconservative substitutions of three to six of the seven critical amino acids of hIL-18BP and neither protein bound hIL-18, suggesting that they may interact with unidentified ligands.Keywords
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