
<ArticleTitle>Correspondence of the functional epitopes of poxvirus and human interleukin-18-binding proteins.</ArticleTitle>
<AbstractText>Molluscum contagiosum virus, a human poxvirus that causes persistent small benign skin tumors, encodes a variety of putative immune defense proteins. Three such proteins, <prot>MC51L</prot>, <prot>MC53L</prot>, and <prot>MC54L</prot>, have 20 to 35% amino acid sequence identities with human <prot><prot>interleukin-18</prot> (<prot>hIL-18</prot>)-binding protein</prot> (<prot>hIL-18BP</prot>), a naturally occurring antagonist of the proinflammatory cytokine <prot>IL-18</prot>. We previously demonstrated that seven amino acids within the immunoglobulin-like domain of <prot>hIL-18BP</prot> were important for high-affinity binding to <prot>hIL-18</prot>. Model building indicated that MC54L, which has been shown to bind <prot>hIL-18</prot>, 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 <prot>MC54L</prot> caused changes in affinity and binding free energy for <prot>hIL-18</prot> that were quantitatively similar to those produced by mutagenesis of <prot>hIL-18BP</prot>. Furthermore, when the nonconserved valine of <prot>MC54L</prot> was mutated to phenylalanine, making it more like <prot>hIL-18BP</prot>, its affinity for <prot>hIL-18</prot> increased more than 10-fold. In addition, the carboxyl-terminal half of <prot>MC54L</prot>, which has no similarity with <prot>hIL-18BP</prot>, was dispensable for <prot>hIL-18</prot> binding. Thus, despite their relatively low overall sequence identity, <prot>MC54L</prot> and <prot>hIL-18BP</prot> have similar <prot>hIL-18</prot> binding sites and functional epitopes. On the other hand, <prot>MC51L</prot> and <prot>MC53L</prot> have nonconservative substitutions of three to six of the seven critical amino acids of <prot>hIL-18BP</prot> and neither protein bound <prot>hIL-18</prot>, suggesting that they may interact with unidentified ligands.</AbstractText>
