Mapping mouse IL-13 binding regions using structure modeling, molecular docking, and high-density peptide microarray analysis.

ABSTRACT: Interleukin-13 is a Th2-associated cytokine responsible for many pathological responses in allergic asthma including mucus production, inflammation, and extracellular matrix remodeling. In addition, IL-13 is required for immunity to many helminth infections. IL-13 signals via the type-II IL-4 receptor, a heterodimeric receptor of IL-13R?1 and IL-4R?, which is also used by IL-4. IL-13 also binds to IL-13R?2, but with much higher affinity than the type-II IL-4 receptor. Binding of IL-13 to IL-13R?2 has been shown to attenuate IL-13 signaling through the type-II IL-4 receptor. However, molecular determinants that dictate the specificity and affinity of mouse IL-13 for the different receptors are largely unknown. Here, we used high-density overlapping peptide arrays, structural modeling, and molecular docking methods to map IL-13 binding sequences on its receptors. Predicted binding sequences on mouse IL-13R?1 and IL-13R?2 were in agreement with the reported human IL-13 receptor complex structures and site-directed mutational analysis. Novel structural differences were identified between IL-13 receptors, particularly at the IL-13 binding interface. Notably, additional binding sites were observed for IL-13 on IL-13R?2. In addition, the identification of peptide sequences that are unique to IL-13R?1 allowed us to generate a monoclonal antibody that selectively binds IL-13R?1. Thus, high-density peptide arrays combined with molecular docking studies provide a novel, rapid, and reliable method to map cytokine-receptor interactions that may be used to generate signaling and decoy receptor-specific antagonists.

SUBMITTER: Madala SK 

PROVIDER: S-EPMC3005206 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature