Research Highlight: Achsah D. Keegan
|Molecular and Structural Basis of Cytokine Receptor Pleiotropy in the Interleukin-4/13 System
Sherry L. LaPorte,1 Z. Sean Juo,1 Jana Vaclavikova,1 Leremy A. Colf,1 Xiulan Qi,2 Nicola M. Heller,2Achsah D. Keegan,2 and K. Christopher Garcia1
1 Howard Hughes Medical Institute, Departments of Molecular and Cellular Physiology, and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
2 Center for Vascular and Inflammatory Diseases and Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
|Copyright © 2008 Cell Press. All rights reserved.
Cell, Vol 132, 259-272, 25 January 2008
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|Interleukin-4 and Interleukin-13 are cytokines critical to the development of T cell-mediated humoral immune responses, which are associated with allergy and asthma, and exert their actions through three different combinations of shared receptors. Here we present the crystal structures of the complete set of type I (IL-4R?/?c/IL-4) and type II (IL-4R?/IL-13R?1/IL-4, IL-4R?/IL-13R?1/IL-13) ternary signaling complexes. The type I complex reveals a structural basis for ?c's ability to recognize six different ?c-cytokines. The two type II complexes utilize an unusual top-mounted Ig-like domain on IL-13R?1 for a novel mode of cytokine engagement that contributes to a reversal in the IL-4 versus IL-13 ternary complex assembly sequences, which are mediated through substantially different recognition chemistries. We also show that the type II receptor heterodimer signals with different potencies in response to IL-4 versus IL-13 and suggest that the extracellular cytokine-receptor interactions are modulating intracellular membrane-proximal signaling events.
Figure 1. Complexes of Helical Cytokines and Their Receptors