Review ArticleThe βc receptor family – Structural insights and their functional implications
Section snippets
Roles of the βc cytokine family in biology and disease
The beta common (βc) family of cytokines consists of granulocyte–macrophage colony stimulating factor (GM-CSF), interleukin (IL)-3 and IL-5. They are produced by activated T-cells to regulate the survival, proliferation, differentiation and functional activation of hematopoietic cells (Fig. 1, reviewed in [1], [2], [3]). GM-CSF can also be expressed by various other cell types, such as macrophages or epithelial cells (reviewed in [1], [2], [3], [4]). GM-CSF acts on many myeloid cells at
General structure of the βc receptor family
The receptor complex for the βc cytokine family consists of a cytokine specific alpha subunit (GMRα, IL3Rα and IL5Rα) and a homodimeric βc subunit shared by the three cytokines (Fig. 2).
The extracellular domains (ECD) of the alpha subunits and βc are each anchored to the cell membrane by a short juxtamembrane (JM) domain connected to a helical transmembrane (TM) domain, followed by the intracellular domain (ICD) (Fig. 3). There is little structural information for the JM domain, TM domain
Crystal structure of open and closed forms of IL3Rα
Our recently published structure of IL3Rα bound to a neutralizing monoclonal antibody revealed for the first time the alpha subunit of the IL-3 receptor complex (Fig. 2, Table 1). Similar to IL5Rα in the IL-5 binary complex structures [34], [35], IL3Rα is comprised of three FnIII domains (NTD, D2 & D3), arranged in a “wrench-like” conformation, with the antibody bound to the NTD [41]. However, to our surprise the crystal revealed two alternate conformations of IL3Rα in the asymmetric unit,
The IL-5 binary complex structure
Both the crystal structure of IL-5 and its binary complex have been published (Fig. 2) [34], [35], [60]. IL-5 is unusual compared to other Type I cytokines in that it exists as a homodimer (134 residues each, I20-S134), whereby the two monomers are held together by hydrophobic, electrostatic and disulfide bonds. The two IL-5 monomers adopt very similar helical folds except for helix D which combines with helices A, B, and C of the second monomer and vice versa. The IL-5 homodimer binds to a
Presentation of the βc cytokine family to the high affinity binding Site 2
The crystal structures of the IL-5 binary complex and the GM-CSF ternary complex (Fig. 2, Table 1), along with binding studies of IL-3 and IL3Rα mutants, demonstrate that the βc family of cytokines present helices A and C to the high affinity binding site on βc (Site 2) [31], [34], [35], [41]. Outside the βc family of cytokines, IL-4, IL-6, IL-13, thymic stromal lymphopoietin and leukemia inhibitory factor also present their A and C helices to the high affinity binding site [63], [72], [73],
Conformational changes observed upon affinity conversion between binary and ternary complexes within the βc family
The way that the NTD wraps around the cytokine in the crystal structures of the IL-5 (Fig. 2, Table 1) [34], [35] and the structurally related IL-13 [63], [64] receptor complexes, and in the closed IL-3 binary complex model [41], suggests that the role of the NTD is to optimally position the cytokine to interact with its high affinity binding receptor. Precisely how the binding of a cytokine to its receptors activates the receptor complex, ultimately triggering downstream signaling events,
Summary and conclusion
Since the discovery of the βc family cytokines in the late 1970s [102] and early 1980s [103], [104] much has been learnt about their biology and involvement in disease. The 1980’s saw the cloning of βc family cytokines, which allowed their large scale production for biological studies in vivo and the determination of their 3D atomic structures in the early 1990’s (Fig. 2). At this time receptor binding studies and the cloning of the receptors themselves revealed the structural relatedness and
Acknowledgments
This work was supported by grants from the National Health and Medical Research Council of Australia (NHMRC) to T.R.H., M.W.P and A.F.L. and from the Australian Cancer Research Foundation to M.W.P. Funding from the Victorian Government Operational Infrastructure Support Scheme to St Vincent’s Institute is acknowledged. S.E.B is a Postdoctoral Fellow supported by the Leukaemia Foundation. U.D. and M.W.P. are NHMRC Postdoctoral and Research Fellows, respectively.
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