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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References
Aravind L, Koonin EV (1999) Gleaning non-trivial structural, functional and evolutionary information about proteins by iterative database searches. J Mol Biol 287:1023–1040. https://doi.org/10.1006/jmbi.1999.2653
Ashkenazy H, Abadi S, Martz E et al (2016) ConSurf 2016: an improved methodology to estimate and visualize evolutionary conservation in macromolecules. Nucleic Acids Res 44:W344–W350. https://doi.org/10.1093/nar/gkw408
Bahadur RP, Chakrabarti P, Rodier F, Janin J (2004) A dissection of specific and non-specific protein–protein interfaces. J Mol Biol 336:943–955. https://doi.org/10.1016/j.jmb.2003.12.073
Bateman A (2019) UniProt: a worldwide hub of protein knowledge. Nucleic Acids Res 47:D506–D515. https://doi.org/10.1093/nar/gky1049
Bazan JF (1990a) Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci USA 87:6934–6938. https://doi.org/10.1073/pnas.87.18.6934
Bazan JF (1990b) Shared architecture of hormone binding domains in type I and II interferon receptors. Cell 61:753–754
Berman HM, Westbrook J, Feng Z et al (2000) The protein data bank. Nucleic Acids Res 28:235–242
Borriello F, Galdiero MR, Varricchi G et al (2019) Innate immune modulation by GM-CSF and IL-3 in health and disease. Int J Mol Sci 20:834
Broughton SE, Hercus TR, Hardy MP et al (2014) Dual mechanism of interleukin-3 receptor blockade by an anti-cancer antibody. Cell Rep 8:410–419. https://doi.org/10.1016/j.celrep.2014.06.038
Broughton SE, Nero TL, Dhagat U et al (2015a) The βc receptor family—structural insights and their functional implications. Cytokine 74:247–258
Broughton SE, Nero TL, Dhagat U et al (2015b) The βc receptor family—structural insights and their functional implications. Cytokine 74:247–258. https://doi.org/10.1016/j.cyto.2015.02.005
Broughton SE, Hercus TR, Nero TL et al (2016) Conformational changes in the GM-CSF receptor suggest a molecular mechanism for affinity conversion and receptor signaling. Structure 24:1271–1281. https://doi.org/10.1016/j.str.2016.05.017
Broughton SE, Hercus TR, Nero TL et al (2018) A dual role for the N-terminal domain of the IL-3 receptor in cell signalling. Nat Commun 9:386. https://doi.org/10.1038/s41467-017-02633-7
Clark-Lewis I, Hood LE, Kent SBH (1988) Role of disulfide bridges in determining the biological activity of interleukin 3. Proc Natl Acad Sci USA 85:7897–7901. https://doi.org/10.1073/pnas.85.21.7897
Crooks GE, Hon G, Chandonia JM, Brenner SE (2004) WebLogo: a sequence logo generator. Genome Res 14:1188–1190. https://doi.org/10.1101/gr.849004
Dagil R, Knudsen MJ, Olsen JG et al (2012) The WSXWS motif in cytokine receptors is a molecular switch involved in receptor activation: insight from structures of the prolactin receptor. Structure 20:270–282. https://doi.org/10.1016/j.str.2011.12.010
Dahl C, Hoffmann HJ, Saito H, Schiøtz PO (2004) Human mast cells express receptors for IL-3, IL-5 and GM-CSF; a partial map of receptors on human mast cells cultured in vitro. Allergy Eur J Allergy Clin Immunol 59:1087–1096. https://doi.org/10.1111/j.1398-9995.2004.00606.x
Doolittle RF (1981) Similar amino acid sequences: chance or common ancestry? Science 214:149–159. https://doi.org/10.1126/science.7280687
Feng Y, Klein BK, McWherter CA (1996) Three-dimensional solution structure and backbone dynamics of a variant of human interleukin-3. J Mol Biol 259:524–541. https://doi.org/10.1006/jmbi.1996.0337
Finn RD, Clements J, Eddy SR (2011) HMMER web server: interactive sequence similarity searching. Nucleic Acids Res 39:W29. https://doi.org/10.1093/nar/gkr367
Gelly JC, de Brevern AG, Hazout S (2006) “Protein peeling”: an approach for splitting a 3D protein structure into compact fragments. Bioinformatics 22:129–133. https://doi.org/10.1093/bioinformatics/bti773
Hercus TR, Dhagat U, Kan WLT et al (2013) Signalling by the βc family of cytokines. Cytokine Growth Factor Rev 24:189–201
Hercus TR, Kan WLT, Broughton SE et al (2018) Role of the β common (βc) family of cytokines in health and disease. Cold Spring Harb Perspect Biol 10:a028514. https://doi.org/10.1101/cshperspect.a028514
Jen EY, Gao X, Li L et al (2020) FDA approval summary: tagraxofusp-erzs for treatment of blastic plasmacytoid dendritic cell neoplasm. Clin Cancer Res 26:532–536. https://doi.org/10.1158/1078-0432.CCR-19-2329
Jurrus E, Engel D, Star K et al (2018) Improvements to the APBS biomolecular solvation software suite. Protein Sci 27:112–128. https://doi.org/10.1002/pro.3280
Kitamura T, Sato N, Arai K, ichi, Miyajima A, (1991) Expression cloning of the human IL-3 receptor cDNA reveals a shared β subunit for the human IL-3 and GM-CSF receptors. Cell 66:1165–1174. https://doi.org/10.1016/0092-8674(91)90039-2
Klein BK, Feng Y, McWherter CA et al (1997) The receptor binding site of human interleukin-3 defined by mutagenesis and molecular modeling. J Biol Chem 272:22630–22641. https://doi.org/10.1074/jbc.272.36.22630
Krissinel E, Henrick K (2007) Inference of macromolecular assemblies from crystalline state. J Mol Biol 372:774–797. https://doi.org/10.1016/j.jmb.2007.05.022
Krivov GG, Shapovalov MV, Dunbrack RL (2009) Improved prediction of protein side-chain conformations with SCWRL4. Proteins Struct Funct Bioinform 77:778–795. https://doi.org/10.1002/prot.22488
Kubasch AS, Schulze F, Giagounidis A et al (2020) Single agent talacotuzumab demonstrates limited efficacy but considerable toxicity in elderly high-risk MDS or AML patients failing hypomethylating agents. Leukemia 34:1182–1186. https://doi.org/10.1038/s41375-019-0645-z
Kusano S, Kukimoto-Niino M, Hino N et al (2012) Structural basis of interleukin-5 dimer recognition by its α receptor. Protein Sci 21:850–864. https://doi.org/10.1002/pro.2072
Lopez AF, Shannon MF, Barry S et al (1992) A human interleukin 3 analog with increased biological and binding activities. Proc Natl Acad Sci USA 89:11842–11846. https://doi.org/10.1073/pnas.89.24.11842
Lopez AF, Hercus TR, Ekert P et al (2010) Molecular basis of cytokine receptor activation. IUBMB Life 62:509–518. https://doi.org/10.1002/iub.350
Lyne PD, Bamborough P, Duncan D, Richards WG (1995) Molecular modeling of the GM-CSF and IL-3 receptor complexes. Protein Sci 4:2223–2233. https://doi.org/10.1002/pro.5560041027
Milburn MV, Hassell AM, Lambert MH et al (1993) A novel dimer configuration revealed by the crystal structure at 2.4 Å resolution of human interleukin-5. Nature 363:172–176. https://doi.org/10.1038/363172a0
Montesinos P, Roboz GJ, Bulabois CE et al (2020) Safety and efficacy of talacotuzumab plus decitabine or decitabine alone in patients with acute myeloid leukemia not eligible for chemotherapy: results from a multicenter, randomized, phase 2/3 study. Leukemia 35:62–74. https://doi.org/10.1038/s41375-020-0773-5
Nicola NA, Hilton DJ (1998) General classes and functions of four-helix bundle cytokines. Adv Protein Chem 52:1–65. https://doi.org/10.1016/s0065-3233(08)60432-5
Quelle DE, Quelle FW, Wojchowski DM (1992) Mutations in the WSAWSE and cytosolic domains of the erythropoietin receptor affect signal transduction and ligand binding and internalization. Mol Cell Biol 12:4553–4561. https://doi.org/10.1128/mcb.12.10.4553
Robert X, Gouet P (2014) Deciphering key features in protein structures with the new ENDscript server. Nucleic Acids Res 42:W320–W324. https://doi.org/10.1093/nar/gku316
Rozwarski DA, Diederichs K, Hecht R et al (1996) Refined crystal structure and mutagenesis of human granulocyte–macrophage colony-stimulating factor. Proteins Struct Funct Genet 26:304–313. https://doi.org/10.1002/(SICI)1097-0134(199611)26:3%3c304::AID-PROT6%3e3.0.CO;2-D
Sachs L (1996) The control of hematopoiesis and leukemia: from basic biology to the clinic. Proc Natl Acad Sci USA 93:4742–4749. https://doi.org/10.1073/pnas.93.10.4742
Šali A, Blundell TL (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234:779–815. https://doi.org/10.1006/jmbi.1993.1626
Schrödinger L (2015) The PyMOL molecular graphics system, version 1.8, Schrödinger, LLC
Scott DE, Bayly AR, Abell C, Skidmore J (2016) Small molecules, big targets: drug discovery faces the protein–protein interaction challenge. Nat Rev Drug Discov 15:533–550. https://doi.org/10.1038/nrd.2016.29
Shin WH, Christoffer CW, Kihara D (2017) In silico structure-based approaches to discover protein-protein interaction-targeting drugs. Methods 131:22–32
Sievers F, Wilm A, Dineen D et al (2011) Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol 7:539. https://doi.org/10.1038/msb.2011.75
Testa U, PelosiCastelli, EG (2019) CD123 as a therapeutic target in the treatment of hematological malignancies. Cancers (basel) 11:1358. https://doi.org/10.3390/cancers11091358
Thomas JW, Baum CM, Hood WF et al (1995) Potent interleukin 3 receptor agonist with selectively enhanced hematopoietic activity relative to recombinant human interleukin 3. Proc Natl Acad Sci USA 92:3779–3783. https://doi.org/10.1073/pnas.92.9.3779
Thompson JD, Higgins DG, Gibson TJ (1994) CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22:4673–4680. https://doi.org/10.1093/nar/22.22.4673
Tina KG, Bhadra R, Srinivasan N (2007) PIC: protein interactions calculator. Nucleic Acids Res 35:W473–W476. https://doi.org/10.1093/nar/gkm423
Uy GL, Aldoss I, Foster MC et al (2020) Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia. Blood. https://doi.org/10.1182/blood.2020007732
Wang X, Lupardus P, LaPorte SL, Garcia KC (2009) Structural biology of shared cytokine receptors. Annu Rev Immunol 27:29–60. https://doi.org/10.1146/annurev.immunol.24.021605.090616
Weber GF, Chousterman BG, He S et al (2015) Interleukin-3 amplifies acute inflammation and is a potential therapeutic target in sepsis. Science 347:1260–1265. https://doi.org/10.1126/science.aaa4268
Yamaguchi T, Schares S, Fischer U, Dijkstra JM (2016) Identification of a fourth ancient member of the IL-3/IL-5/GM-CSF cytokine family, KK34, in many mammals. Dev Comp Immunol 65:268–279. https://doi.org/10.1016/j.dci.2016.07.018
Yao S, Young IG, Norton RS, Murphy JM (2011) Murine interleukin-3: structure, dynamics, and conformational heterogeneity in solution. Biochemistry 50:2464–2477. https://doi.org/10.1021/bi101810f
Zhang Y, Skolnick J (2005) TM-align: a protein structure alignment algorithm based on the TM-score. Nucleic Acids Res 33:2302–2309. https://doi.org/10.1093/nar/gki524
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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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