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Structural and evolutionary exploration of the IL-3 family and its alpha subunit receptors

Abstract

Interleukin-3 (IL-3) is a cytokine belonging to the family of common β (βc) and is involved in various biological systems. Its activity is mediated by the interaction with its receptor (IL-3R), a heterodimer composed of two distinct subunits: IL-3Rα and βc. IL-3 and its receptor, especially IL-3Rα, play a crucial role in pathologies like inflammatory diseases and therefore are interesting therapeutic targets. Here, we have performed an analysis of these proteins and their interaction based on structural and evolutionary information. We highlighted that IL-3 and IL-3Rα structural architectures are conserved across evolution and shared with other proteins belonging to the same βc family interleukin-5 (IL-5) and granulocyte–macrophage colony-stimulating factor (GM-CSF). The IL-3Rα/IL-3 interaction is mediated by a large interface in which most residues are surprisingly not conserved during evolution and across family members. In spite of this high variability, we suggested small regions constituted by few residues conserved during the evolution in both proteins that could be important for the binding affinity.

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Acknowledgements

The research was supported by the French National Research Agency with grant ANR-19-CE17-0021 (BASIN) for J.F., J.B., J.D. & A.G.d.B., the Laboratory of Excellence GR-Ex, reference ANR-11-LABX-0051, and the program “Investissements d’avenir” of the French National Research Agency, reference ANR-11-IDEX-0005-02 for J.F., J.D. and A.G.d.B, the Indo-French Centre for the Promotion of Advanced Research / CEFIPRA for collaborative grants (numbers 5302-2) for A.G.d.B. The funding bodies have no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

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Correspondence to Julien Diharce or Alexandre G. de Brevern.

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Fogha, J., Bayry, J., Diharce, J. et al. Structural and evolutionary exploration of the IL-3 family and its alpha subunit receptors. Amino Acids 53, 1211–1227 (2021). https://doi.org/10.1007/s00726-021-03026-3

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  • DOI: https://doi.org/10.1007/s00726-021-03026-3

Keywords

  • IL-3
  • IL-3Rα
  • Evolutionary conservation
  • Protein structures
  • Protein–-protein interactions