Structure of the Interleukin-5 Receptor Complex Exemplifies the Organizing Principle of Common Beta Cytokine Signaling

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2024 Apr 13

PMID 38614096

Authors

Nathanael A Caveney

Grayson E Rodriguez

Christoph Pollmann

Thomas Meyer

Marta T Borowska

Steven C Wilson

Nan Wang

Xinyu Xiang

Karsten D Householder

Pingdong Tao

Leon L Su

Robert A Saxton

Jacob Piehler

K Christopher Garcia

Affiliations

Soon will be listed here.

Abstract

Cytokines regulate immune responses by binding to cell surface receptors, including the common subunit beta (βc), which mediates signaling for GM-CSF, IL-3, and IL-5. Despite known roles in inflammation, the structural basis of IL-5 receptor activation remains unclear. We present the cryo-EM structure of the human IL-5 ternary receptor complex, revealing architectural principles for IL-5, GM-CSF, and IL-3. In mammalian cell culture, single-molecule imaging confirms hexameric IL-5 complex formation on cell surfaces. Engineered chimeric receptors show that IL-5 signaling, as well as IL-3 and GM-CSF, can occur through receptor heterodimerization, obviating the need for higher-order assemblies of βc dimers. These findings provide insights into IL-5 and βc receptor family signaling mechanisms, aiding in the development of therapies for diseases involving deranged βc signaling.

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References

Wedeking T, Lochte S, Birkholz O, Wallenstein A, Trahe J, Klingauf J . Spatiotemporally Controlled Reorganization of Signaling Complexes in the Plasma Membrane of Living Cells. Small. 2015; 11(44):5912-8. DOI: 10.1002/smll.201502132. View

Serge A, Bertaux N, Rigneault H, Marguet D . Dynamic multiple-target tracing to probe spatiotemporal cartography of cell membranes. Nat Methods. 2008; 5(8):687-94. DOI: 10.1038/nmeth.1233. View

Emsley P, Cowtan K . Coot: model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr. 2004; 60(Pt 12 Pt 1):2126-32. DOI: 10.1107/S0907444904019158. View

Bellon J, Birkholz O, Richter C, Eull F, Kenneweg H, Wilmes S . Four-color single-molecule imaging with engineered tags resolves the molecular architecture of signaling complexes in the plasma membrane. Cell Rep Methods. 2022; 2(2):100165. PMC: 9017138. DOI: 10.1016/j.crmeth.2022.100165. View

Gotzke H, Kilisch M, Martinez-Carranza M, Sograte-Idrissi S, Rajavel A, Schlichthaerle T . The ALFA-tag is a highly versatile tool for nanobody-based bioscience applications. Nat Commun. 2019; 10(1):4403. PMC: 6764986. DOI: 10.1038/s41467-019-12301-7. View

Wilmes S, Hafer M, Vuorio J, Tucker J, Winkelmann H, Lochte S . Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations. Science. 2020; 367(6478):643-652. PMC: 8117407. DOI: 10.1126/science.aaw3242. View

Lochte S, Waichman S, Beutel O, You C, Piehler J . Live cell micropatterning reveals the dynamics of signaling complexes at the plasma membrane. J Cell Biol. 2014; 207(3):407-18. PMC: 4226739. DOI: 10.1083/jcb.201406032. View

Broughton S, Hercus T, Hardy M, McClure B, Nero T, Dottore M . Dual mechanism of interleukin-3 receptor blockade by an anti-cancer antibody. Cell Rep. 2014; 8(2):410-9. DOI: 10.1016/j.celrep.2014.06.038. View

Patino E, Kotzsch A, Saremba S, Nickel J, Schmitz W, Sebald W . Structure analysis of the IL-5 ligand-receptor complex reveals a wrench-like architecture for IL-5Rα. Structure. 2011; 19(12):1864-75. DOI: 10.1016/j.str.2011.08.015. View

10.

Sockolosky J, Trotta E, Parisi G, Picton L, Su L, Le A . Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes. Science. 2018; 359(6379):1037-1042. PMC: 5947856. DOI: 10.1126/science.aar3246. View

11.

Kan W, Dhagat U, Kaufmann K, Hercus T, Nero T, Zeng A . Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia. Cancer Discov. 2023; 13(8):1922-1947. PMC: 10401075. DOI: 10.1158/2159-8290.CD-22-1396. View

12.

Carr P, Conlan F, Ford S, Ollis D, Young I . An improved resolution structure of the human beta common receptor involved in IL-3, IL-5 and GM-CSF signalling which gives better definition of the high-affinity binding epitope. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2006; 62(Pt 6):509-13. PMC: 2243076. DOI: 10.1107/S1744309106016812. View

13.

Punjani A, Rubinstein J, Fleet D, Brubaker M . cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat Methods. 2017; 14(3):290-296. DOI: 10.1038/nmeth.4169. View

14.

You C, Marquez-Lago T, Richter C, Wilmes S, Moraga I, Garcia K . Receptor dimer stabilization by hierarchical plasma membrane microcompartments regulates cytokine signaling. Sci Adv. 2016; 2(12):e1600452. PMC: 5135388. DOI: 10.1126/sciadv.1600452. View

15.

Chen V, Arendall 3rd W, Headd J, Keedy D, Immormino R, Kapral G . MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 1):12-21. PMC: 2803126. DOI: 10.1107/S0907444909042073. View

16.

Mirdita M, Schutze K, Moriwaki Y, Heo L, Ovchinnikov S, Steinegger M . ColabFold: making protein folding accessible to all. Nat Methods. 2022; 19(6):679-682. PMC: 9184281. DOI: 10.1038/s41592-022-01488-1. View

17.

Broughton S, Hercus T, Nero T, Dottore M, McClure B, Dhagat U . Conformational Changes in the GM-CSF Receptor Suggest a Molecular Mechanism for Affinity Conversion and Receptor Signaling. Structure. 2016; 24(8):1271-1281. DOI: 10.1016/j.str.2016.05.017. View

18.

Wilson S, Caveney N, Yen M, Pollmann C, Xiang X, Jude K . Organizing structural principles of the IL-17 ligand-receptor axis. Nature. 2022; 609(7927):622-629. PMC: 9477748. DOI: 10.1038/s41586-022-05116-y. View

19.

Los G, Encell L, McDougall M, Hartzell D, Karassina N, Zimprich C . HaloTag: a novel protein labeling technology for cell imaging and protein analysis. ACS Chem Biol. 2008; 3(6):373-82. DOI: 10.1021/cb800025k. View

20.

Saxton R, Caveney N, Moya-Garzon M, Householder K, Rodriguez G, Burdsall K . Structural insights into the mechanism of leptin receptor activation. Nat Commun. 2023; 14(1):1797. PMC: 10066393. DOI: 10.1038/s41467-023-37169-6. View