Structural insights into the assembly and activation of the IL-27 signaling complex

Yibo Jin; Paul K. Fyfe; Scott Gardner; Stephan Wilmes; Doryen Bubeck; Ignacio Moraga

doi:10.15252/embr.202255450

Structural insights into the assembly and activation of the IL-27 signaling complex

Yibo Jin, Paul K. Fyfe, Scott Gardner, Stephan Wilmes, Doryen Bubeck (Lead / Corresponding author), Ignacio Moraga (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

14 Citations (Scopus)

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Abstract

Interleukin 27 (IL-27) is a heterodimeric cytokine that elicits potent immunosuppressive responses. Comprised of EBI3 and p28 subunits, IL-27 binds GP130 and IL-27Rα receptor chains to activate the JAK/STAT signaling cascade. However, how these receptors recognize IL-27 and form a complex capable of phosphorylating JAK proteins remains unclear. Here, we used cryo electron microscopy (cryoEM) and AlphaFold modeling to solve the structure of the IL-27 receptor recognition complex. Our data show how IL-27 serves as a bridge connecting IL-27Rα (domains 1-2) with GP130 (domains 1-3) to initiate signaling. While both receptors contact the p28 component of the heterodimeric cytokine, EBI3 stabilizes the complex by binding a positively charged surface of IL-27Rα and Domain 1 of GP130. We find that assembly of the IL-27 receptor recognition complex is distinct from both IL-12 and IL-6 cytokine families and provides a mechanistic blueprint for tuning IL-27 pleiotropic actions.

Original language	English
Article number	e55450
Number of pages	10
Journal	EMBO Reports
Volume	23
Issue number	10
Early online date	3 Aug 2022
DOIs	https://doi.org/10.15252/embr.202255450
Publication status	Published - 6 Oct 2022

Keywords

GP130
IL-27
cryo electron microscopy
cytokine

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Genetics

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10.15252/embr.202255450Licence: CC BY

Final Published VersionFinal published version, 5.6 MBLicence: CC BY

Mapping Cytokine Signalling Networks using Engineered Surrogate Ligands (Sir Henry Dale Fellowship)
Crocker, P. (Investigator) & Moraga Gonzalez, I. (Investigator)
1/09/16 → 31/08/22
Project: Research

Cite this

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title = "Structural insights into the assembly and activation of the IL-27 signaling complex",

abstract = "Interleukin 27 (IL-27) is a heterodimeric cytokine that elicits potent immunosuppressive responses. Comprised of EBI3 and p28 subunits, IL-27 binds GP130 and IL-27Rα receptor chains to activate the JAK/STAT signaling cascade. However, how these receptors recognize IL-27 and form a complex capable of phosphorylating JAK proteins remains unclear. Here, we used cryo electron microscopy (cryoEM) and AlphaFold modeling to solve the structure of the IL-27 receptor recognition complex. Our data show how IL-27 serves as a bridge connecting IL-27Rα (domains 1-2) with GP130 (domains 1-3) to initiate signaling. While both receptors contact the p28 component of the heterodimeric cytokine, EBI3 stabilizes the complex by binding a positively charged surface of IL-27Rα and Domain 1 of GP130. We find that assembly of the IL-27 receptor recognition complex is distinct from both IL-12 and IL-6 cytokine families and provides a mechanistic blueprint for tuning IL-27 pleiotropic actions.",

keywords = "GP130, IL-27, cryo electron microscopy, cytokine",

author = "Yibo Jin and Fyfe, {Paul K.} and Scott Gardner and Stephan Wilmes and Doryen Bubeck and Ignacio Moraga",

note = "Funding Information: We thank members of the Moraga and Bubeck laboratories for helpful advice and discussion. This work was supported by the Wellcome-Trust-202323/Z/16/Z (IM), ERC-206-STG grant (IM, PKF, SW). We thank S. Islam for computational support and P. Simpson for EM support. Initial screening of samples was carried out at Imperial College London Centre for Structural Biology, Research Complex at Harwell and LonCEM (Francis Crick Institute); cryoEM data used to calculate the final reconstruction was collected at Diamond Light Source. We thank Diamond for access and support of the Cryo-EM facilities at the UK national electron bio-imaging centre (eBIC), proposal BI25127, funded by the Wellcome Trust, Medical Research Council and BBSRC. We also wish to thank R. Sundaramoorthy for his assistance in the initial stages of the project. Copyright; {\textcopyright} 2022 The Authors. Published under the terms of the CC BY 4.0 license.",

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AU - Gardner, Scott

AU - Wilmes, Stephan

AU - Bubeck, Doryen

AU - Moraga, Ignacio

N1 - Funding Information: We thank members of the Moraga and Bubeck laboratories for helpful advice and discussion. This work was supported by the Wellcome-Trust-202323/Z/16/Z (IM), ERC-206-STG grant (IM, PKF, SW). We thank S. Islam for computational support and P. Simpson for EM support. Initial screening of samples was carried out at Imperial College London Centre for Structural Biology, Research Complex at Harwell and LonCEM (Francis Crick Institute); cryoEM data used to calculate the final reconstruction was collected at Diamond Light Source. We thank Diamond for access and support of the Cryo-EM facilities at the UK national electron bio-imaging centre (eBIC), proposal BI25127, funded by the Wellcome Trust, Medical Research Council and BBSRC. We also wish to thank R. Sundaramoorthy for his assistance in the initial stages of the project. Copyright; © 2022 The Authors. Published under the terms of the CC BY 4.0 license.

PY - 2022/10/6

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N2 - Interleukin 27 (IL-27) is a heterodimeric cytokine that elicits potent immunosuppressive responses. Comprised of EBI3 and p28 subunits, IL-27 binds GP130 and IL-27Rα receptor chains to activate the JAK/STAT signaling cascade. However, how these receptors recognize IL-27 and form a complex capable of phosphorylating JAK proteins remains unclear. Here, we used cryo electron microscopy (cryoEM) and AlphaFold modeling to solve the structure of the IL-27 receptor recognition complex. Our data show how IL-27 serves as a bridge connecting IL-27Rα (domains 1-2) with GP130 (domains 1-3) to initiate signaling. While both receptors contact the p28 component of the heterodimeric cytokine, EBI3 stabilizes the complex by binding a positively charged surface of IL-27Rα and Domain 1 of GP130. We find that assembly of the IL-27 receptor recognition complex is distinct from both IL-12 and IL-6 cytokine families and provides a mechanistic blueprint for tuning IL-27 pleiotropic actions.

AB - Interleukin 27 (IL-27) is a heterodimeric cytokine that elicits potent immunosuppressive responses. Comprised of EBI3 and p28 subunits, IL-27 binds GP130 and IL-27Rα receptor chains to activate the JAK/STAT signaling cascade. However, how these receptors recognize IL-27 and form a complex capable of phosphorylating JAK proteins remains unclear. Here, we used cryo electron microscopy (cryoEM) and AlphaFold modeling to solve the structure of the IL-27 receptor recognition complex. Our data show how IL-27 serves as a bridge connecting IL-27Rα (domains 1-2) with GP130 (domains 1-3) to initiate signaling. While both receptors contact the p28 component of the heterodimeric cytokine, EBI3 stabilizes the complex by binding a positively charged surface of IL-27Rα and Domain 1 of GP130. We find that assembly of the IL-27 receptor recognition complex is distinct from both IL-12 and IL-6 cytokine families and provides a mechanistic blueprint for tuning IL-27 pleiotropic actions.

KW - GP130

KW - IL-27

KW - cryo electron microscopy

KW - cytokine

U2 - 10.15252/embr.202255450

DO - 10.15252/embr.202255450

M3 - Article

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SN - 1469-221X

VL - 23

JO - EMBO Reports

JF - EMBO Reports

IS - 10

M1 - e55450

ER -

Structural insights into the assembly and activation of the IL-27 signaling complex

Abstract

Keywords

ASJC Scopus subject areas

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Projects

Mapping Cytokine Signalling Networks using Engineered Surrogate Ligands (Sir Henry Dale Fellowship)

Cite this