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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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Article Summary
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.

keegan Research image

Figure 1. Complexes of Helical Cytokines and Their Receptors

  1. Complex of human growth hormone (hGH) with two identical receptor (GHR) molecules. The complex contains two ligand-receptor interfaces (I and II) located on the opposite sides of hGH, as well as the third inter-receptor interface (III) formed by the C-terminal regions of the receptors located in the proximity of the plasma membrane. The arrangement of the receptor molecules in the complex shows approximate two-fold symmetry, although the ligand itself is completely asymmetric.
  2. IL-4 and IL-13 are short four-helix bundle cytokines ([Rozwarski et al., 1994] and [Presnell and Cohen, 1989]) sharing 25% sequence identity. Depicted are complexes studied by LaPorte et al. (2008). (Left) The type I complex of IL-4 with IL-4R? and ?c; (middle) the type II complex of IL-4 with IL-4R? and IL-13R?1; (right) the type II complex of IL-13 with IL-4R? and IL-13R?1. The cytokines IL-4 and IL-13 play critical roles in allergy and asthma by binding to different combinations of shared receptors. LaPorte et al. determined the three-dimensional structures of three cytokine-receptor complexes that comprise the IL-4/IL-13 system. These findings define the molecular basis of receptor and ligand “sharing” and revealed unexpectedly different assembly properties of the signaling complexes on cell surfaces that could impact function. Collectively, these studies show that extracellular receptor-ligand interactions are not simply “on/off” switches for signal transduction, but may instigate divergent signaling responses through shared receptors, which could be utilized in developing therapeutic agents targeting this receptor system.