Crystal Structure of the Interleukin-4/Receptor α Chain Complex Reveals a Mosaic Binding Interface

@article{Hage1999CrystalSO,
  title={Crystal Structure of the Interleukin-4/Receptor $\alpha$ Chain Complex Reveals a Mosaic Binding Interface},
  author={T. Hage and W. Sebald and P. Reinemer},
  journal={Cell},
  year={1999},
  volume={97},
  pages={271-281}
}
Interleukin-4 (IL-4) is a principal regulatory cytokine during an immune response and a crucial determinant for allergy and asthma. IL-4 binds with high affinity and specificity to the ectodomain of the IL-4 receptor alpha chain (IL4-BP). Subsequently, this intermediate complex recruits the common gamma chain (gamma c), thereby initiating transmembrane signaling. The crystal structure of the intermediate complex between human IL-4 and IL4-BP was determined at 2.3 A resolution. It reveals a… Expand
The Structure of the Interleukin-15α Receptor and Its Implications for Ligand Binding*
TLDR
The model shows that, rather than the familiar hydrophobic forces dominating the interaction interface between cytokines and their cognate receptors, the interaction between the IL-15 andIL-15Rα complex involves a large network of ionic interactions, which is essential for the biological effects of this important cytokine. Expand
Structure of the Quaternary Complex of Interleukin-2 with Its α, ß, and γc Receptors
TLDR
The structure of γc provides a rationale for loss-of-function mutations found in patients with X-linked severe combined immunodeficiency diseases (X-SCID) and provides a framework for other γ c-dependent cytokine-receptor interactions and for the engineering of improved IL-2 therapeutics. Expand
Molecular and Structural Basis of Cytokine Receptor Pleiotropy in the Interleukin-4/13 System
TLDR
The crystal structures of the complete set of type I and type II type I receptor heterodimer signals with different potencies in response to IL-4 versus IL-13 suggest that the extracellular cytokine-receptor interactions are modulating intracellular membrane-proximal signaling events. Expand
Structural reorganization of the interleukin-7 signaling complex
TLDR
An unliganded receptor structure in the common gamma-chain (γc) family of receptors and cytokines is reported and a molecular mechanism can be used to explain recently discovered IL-7– and γc-independent gain-of-function mutations inIL-7Rα from B- and T-cell acute lymphoblastic leukemia patients. Expand
Functional epitope of common γ chain for interleukin-4 binding
TLDR
The alanine-scanning mutational analysis results provide a basis for elucidating the molecular recognition mechanism in the IL-4 receptor system and a paradigm for other γc-dependent cytokine receptor systems. Expand
Structure, binding, and antagonists in the IL-4/IL-13 receptor system.
TLDR
Detailed knowledge of the site of interaction of IL-4 andIL-4Ralpha has been gained by structure analysis of the complex of these two proteins and through functional studies employing mutants of IL -4 and its receptor subunits, and the hitherto elusive goal of designing small molecular mimetics may be feasible. Expand
Solution structure of human IL-13 and implication for receptor binding.
TLDR
Based on the available structural and mutational data, an IL-13/IL-4Ralpha model and a sequential mechanism for forming the signaling heterodimer is proposed forIL-13. Expand
Structure analysis of the IL-5 ligand-receptor complex reveals a wrench-like architecture for IL-5Rα.
TLDR
The structure demonstrates that for steric reasons, homodimeric IL-5 can bind only one receptor molecule, even though two equivalent receptor-binding sites exist, and advances in molecular understanding provided by this structure are of greatest value. Expand
Solution structure of interleukin-13 and insights into receptor engagement.
TLDR
The first experimentally determined high-resolution structure of human interleukin-13 (IL-13) is reported, significantly different from an earlier homology model, which could have led to improper estimation of receptor interaction surfaces and design of mutational experiments. Expand
The high-affinity interaction of human IL-4 and the receptor alpha chain is constituted by two independent binding clusters.
IL4-BP, the extracellular binding domain of the IL-4 receptor alpha chain, contains a high-affinity binding epitope for IL-4 (K(D) 150 pM). Previous results on the crystal structure of theExpand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 78 REFERENCES
The interleukin‐4 site‐2 epitope determining binding of the common receptor γ chain
TLDR
The present results are in accordance with a two-step-dimerisation mechanism forIL-4 receptor activation, where solute IL-4 at physiological concentrations binds first via the high-affinity site 1 to the α chain only, since the affinity of IL- 4 site 2 for γc is too low. Expand
Crystals of a 1:1 complex between human interleukin-4 and the extracellular domain of its receptor alpha chain.
TLDR
The crystals are isomorphous to that of the complex with normal IL-4 and therefore can be used to solve the crystallographic phase problem by the method of multiple anomalous diffraction (MAD). Expand
A mixed-charge pair in human interleukin 4 dominates high-affinity interaction with the receptor alpha chain.
  • Y. Wang, B. Shen, W. Sebald
  • Biology, Medicine
  • Proceedings of the National Academy of Sciences of the United States of America
  • 1997
TLDR
It is revealed that the high-affinity binding of IL-4 originates from a continuous patch of a few mostly polar or charged amino acid side chains located on helices A and C, which provides the basis for an understanding of molecular recognition in cytokine receptor complexes and for anIL-4 antagonist design. Expand
Global and Local Determinants for the Kinetics of Interleukin‐4/Interleukin‐4 Receptor α Chain Interaction
An engineered interleukin-4-binding protein (IL4-BP) representing the extracellular domain of the human interleukin-4 (IL-4) receptor α chain was expressed in Sf9 cells. The purified IL4-BP wasExpand
Global and local determinants for the kinetics of interleukin-4/interleukin-4 receptor alpha chain interaction. A biosensor study employing recombinant interleukin-4-binding protein.
TLDR
The results indicate that the high-affinity binding of IL-4 to its receptor (Kd approximately 100 pM) is mainly the result of an unusually high association rate. Expand
The interleukin-2 and interleukin-4 receptors studied by molecular modelling.
TLDR
The models offer structural explanations for observed behaviour such as the effects of mutation of the A- and D-helices of the cytokines and may be of use in the identification of residues which may interact in the ligand-receptor interfaces, and which would be worthy of further investigation. Expand
The interleukin-2 receptor gamma chain: its role in the multiple cytokine receptor complexes and T cell development in XSCID.
TLDR
The molecular identification of the gamma chain brought a grasp of the structures and functions of the cytokine receptor and an in-depth understanding of the cause of human XSCID. Expand
Interleukin-2 receptor gamma chain: a functional component of the interleukin-4 receptor.
TLDR
The observation thatIL-2R gamma is a functional component of the IL-4 receptor, together with the finding that IL- 2R gamma associates with theIL-7 receptor, begins to elucidate why deficiency of this common gamma chain has a profound effect on lymphoid function and development, as seen in X-linked severe combined immunodeficiency. Expand
Sharing of the interleukin-2 (IL-2) receptor gamma chain between receptors for IL-2 and IL-4.
TLDR
The results suggest that theIL-2 receptor gamma chain is functionally involved in the IL-4 receptor complex, which is an indispensable subunit for IL-2 binding and intracellular signal transduction. Expand
A model of the complex between interleukin‐4 and its receptors
A three‐dimensional model of interleukin‐4 (IL‐4) bound to one molecule each of the high‐ and low‐affinity receptors (IL‐4R and IL‐2Rγ) was built, using the crystal structure of the complex of humanExpand
...
1
2
3
4
5
...