期刊
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
卷 79, 期 1, 页码 282-293出版社
WILEY
DOI: 10.1002/prot.22881
关键词
cytokine receptors; peptide arrays; protein-protein interactions; structure and protein modeling
资金
- NIH, NIAID
- Medical Research Council [MC_UP_A253_1028] Funding Source: researchfish
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZIAAI000829] Funding Source: NIH RePORTER
- MRC [MC_UP_A253_1028] Funding Source: UKRI
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 alpha 1 and IL-4R alpha, which is also used by IL-4. IL-13 also binds to IL-13R alpha 2, but with much higher affinity than the type-II IL-4 receptor. Binding of IL-13 to IL-13R alpha 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 alpha 1 and IL-13R alpha 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 alpha 2. In addition, the identification of peptide sequences that are unique to IL-13R alpha 1 allowed us to generate a monoclonal antibody that selectively binds IL-13R alpha 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. Proteins 2011; 79: 282-293. Published 2010 Wiley-Liss, Inc.
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