Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15
Copyright policy )Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15
Interleukin 15 (IL-15) and IL-2 have distinct immunological functions even though both signal through the receptor subunit IL-2Rβ and the common γ-chain (γ(c)). Here we found that in the structure of the IL-15-IL-15Rα-IL-2Rβ-γ(c) quaternary complex, IL-15 binds to IL-2Rβ and γ(c) in a heterodimer nearly indistinguishable from that of the IL-2-IL-2Rα-IL-2Rβ-γ(c) complex, despite their different receptor-binding chemistries. IL-15Rα substantially increased the affinity of IL-15 for IL-2Rβ, and this allostery was required for IL-15 trans signaling. Consistent with their identical IL-2Rβ-γ(c) dimer geometries, IL-2 and IL-15 showed similar signaling properties in lymphocytes, with any differences resulting from disparate receptor affinities. Thus, IL-15 and IL-2 induced similar signals, and the cytokine specificity of IL-2Rα versus IL-15Rα determined cellular responsiveness. Our results provide new insights for the development of specific immunotherapeutics based on IL-15 or IL-2.
- National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA United States
- Stanford University United States
- STANFORD UNIVERSITY
- Stanford University School of Medicine United States
- National Institutes of Health United States
Interleukin-15, Models, Molecular, Binding Sites, Interleukin-2 Receptor alpha Subunit, Molecular Dynamics Simulation, Crystallography, X-Ray, Ligands, Interleukin-2 Receptor beta Subunit, Mice, Cell Line, Tumor, Animals, Humans, Interleukin-2, Lymphocytes, Protein Multimerization, Protein Structure, Quaternary, Protein Binding, Signal Transduction
Interleukin-15, Models, Molecular, Binding Sites, Interleukin-2 Receptor alpha Subunit, Molecular Dynamics Simulation, Crystallography, X-Ray, Ligands, Interleukin-2 Receptor beta Subunit, Mice, Cell Line, Tumor, Animals, Humans, Interleukin-2, Lymphocytes, Protein Multimerization, Protein Structure, Quaternary, Protein Binding, Signal Transduction
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