Structural insights into the common γ‐chain family of cytokines and receptors from the interleukin‐7 pathway

Abstract

SUMMARY Over the past 13 years, numerous crystal structures of complexes of the common γ-chain (γc) cytokine receptors and their cytokines have been solved. Even with the remarkable progress in the structural biology of γc receptors and their cytokines or interleukins, there are valuable lessons to be learned from the structural and biophysical studies of interleukin-7 (IL-7) and its α-receptor (IL-7Rα) and comparisons to other γc family members. The structure of the IL-7/IL-7Rα complex teaches that interfaces between the γc interleukins and their receptors can vary in size, polarity, and specificity, and that significant conformational changes might be necessary for complexes of interleukins and their receptors to bind the shared, activating γc receptor. Binding, kinetic, and thermodynamic studies of IL-7 and IL-7Rα show that glycosylation and electrostatics can be important to interactions between ILs and their receptor, even where the glycans and charged residues are distant from the interface. The structure of the IL-7Rα homodimer is a reminder that often-ignored non-activating complexes likely perform roles just as important to signaling as activating complexes. And last but not least, the structural and biophysical studies help explain and potentially treat the diseases caused by aberrant IL-7 signaling.

Membrane Microdomains and Cytoskeleton Organization Shape and Regulate the IL-7 Receptor Signalosome in Human CD4 T-cells

“…3 (a, d, and f) and 7a). When IL-7 is added and binds to its receptor, the IL-7R␣⅐␥c ectodomains change shape, pull the long transmembrane domains closer together, and then bring their endodomains into close proximity, as proposed by Walsh and colleagues (6,23) and summarized in Fig. 7, g-i.…”

“…It binds to a heterodimeric receptor, IL-7R, made up of two glycosylated subunits: IL-7R␣ (CD127, 65 kDa) (4), specific to IL-7 and thymic stromal lymphopoietin (5), and the common ␥ chain (␥c, CD132, 56 kDa) shared by IL-2, 4, 7, 9, 15 and 21 receptors (2). These two chains have common ancestors and share the same topology; both chains are embedded in the membrane by a single-pass transmembrane helix that connects the immunoglobin fold structured ectodomain to the unstructured cytoplasmic domain (6).…”

Comparison of the purification of biologically active IL-7 cytokine expressed in Escherichia coli and Pichia pastoris

“…By acting as a competitive inhibitor to the formation of the ternary complex this IL-7 mutant might modulate, but not block, IL-7 signaling. Besides presenting a possible therapeutic option, this approach would lead to further insights into the interaction between IL-7 and its receptor, validating and complementing the structural data of the IL-7 and the IL-7Ra cocrystal [6,8,18,19].…”

Crystal Structure of a Complex of the Intracellular Domain of Interferon λ Receptor 1 (IFNLR1) and the FERM/SH2 Domains of Human JAK1

“…However, deeper understanding of how the JAK/STAT signaling pathways achieve specificities necessary to control and coordinate complex biological processes in which they participate requires further, more detailed and extensive studies. In contrast to a large number of structures reported for cytokines and interferons [8–10], their complexes with the ectodomains of cytokine/interferon receptors [5, 11–14], and of the kinase [15] and pseudokinase [16] domains of JAKs, structural data for the regions corresponding to the JAK-receptor interface are very limited. The crystal structure of TYK2(FERM-SH2) fragment with a short peptide derived from the IFN-α receptor 1 (IFNAR1) was the first published report addressing this topic [17].…”