PMID: 20223216

 

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Title : Molecular basis for shared cytokine recognition revealed in the structure of an unusually high affinity complex between IL-13 and IL-13Ralpha2

Abstract :

1. Interleukin-13 is a cytokine important for development of T helper cell type 2 (Th2 ) responses and plays a critical role in asthma and allergy
2. The IL-13 Receptor alpha2 ( IL-13Ralpha2 ) is a receptor for IL-13 lacking canonical Jak/STAT signaling functions
3. Here we present the crystal structure along with a mutational and biophysical analysis of the IL-13 / IL-13Ralpha2 complex
4. While retaining a similar mode of IL-13 binding to its related signaling receptor , IL-13Ralpha1 , IL-13Ralpha2 uses peripheral receptor residues unused in the IL-13 / IL-13Ralpha1 complex to generate a larger and more complementary interface for IL-13
5. This results in a four orders of magnitude increase in affinity, to the femtomolar level, compared to IL-13Ralpha1
6. Alanine scanning mutagenesis of the IL-13 interface reveals several common "hotspot" residues important for binding to both receptors, but also identifies a prominent IL-13Ralpha2-specific contact
7. These results provide a framework for development of receptor subtype-selective IL-13 antagonists and indicate a decoy function for IL-13Ralpha2