Journal
CELL
Volume 132, Issue 2, Pages 259-272Publisher
CELL PRESS
DOI: 10.1016/j.cell.2007.12.030
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Funding
- Howard Hughes Medical Institute Funding Source: Medline
- NHLBI NIH HHS [T32 HL007698] Funding Source: Medline
- NIAID NIH HHS [R37 AI051321, R01 AI051321-05, R01 AI038985, R01 AI051321, AI38985, R29 AI038985, AI51321] Funding Source: Medline
- PHS HHS [HHMI_GARCIA_K] Funding Source: Medline
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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 alpha/gamma(c)/IL-4) and type II (IL-4R alpha/IL-13R alpha 1/ IL-4, IL-4R alpha/IL-13R alpha 1/IL-13) ternary signaling complexes. The type I complex reveals a structural basis for gamma(c)'s ability to recognize six different gamma(c)-cytokines. The two type II complexes utilize an unusual top-mounted Ig-like domain on IL-13R alpha 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.
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