Dimeric structure of the pseudokinase IRAK3 suggests an allosteric mechanism for negative regulation

Sven Lange; Marina I. Nelen; Philip Cohen; Yogesh Kulathu

doi:10.1016/j.str.2020.11.004

Dimeric structure of the pseudokinase IRAK3 suggests an allosteric mechanism for negative regulation

Sven Lange, Marina I. Nelen, Philip Cohen (Lead / Corresponding author), Yogesh Kulathu (Lead / Corresponding author)

MRC PPU

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Abstract

Interleukin-1 receptor associated kinases (IRAKs) are key players in innate immune signaling that mediate the host response to pathogens. In contrast to the active kinases IRAK1 and IRAK4, IRAK2 and IRAK3 are pseudokinases lacking catalytic activity and their functions are poorly understood. IRAK3 is thought to be a negative regulator of innate immune signaling and mutations in IRAK3 are associated with asthma and cancer. Here, we report the crystal structure of the human IRAK3 pseudokinase domain in a closed, pseudoactive conformation. IRAK3 dimerizes in a unique way through a head-to-head arrangement not observed in any other kinases. Multiple conserved cysteine residues imply a potential redox control of IRAK3 conformation and dimerization. By analyzing asthma-associated mutations, we identify an evolutionarily conserved surface on IRAK3 that could form an interaction interface with IRAK4, suggesting a model for the negative regulation of IRAK4 by IRAK3.

Original language	English
Pages (from-to)	238-251.e4
Number of pages	14
Journal	Structure
Volume	29
Issue number	3
Early online date	24 Nov 2020
DOIs	https://doi.org/10.1016/j.str.2020.11.004
Publication status	Published - 4 Mar 2021

Keywords

IRAK kinases
Myddosome
Toll-like/Interleukin-1 receptor signalling
asthma
innate immunity
kinase
kinase inhibitors
protein phosphorylation
pseudoenzymes
signal transduction

ASJC Scopus subject areas

Structural Biology
Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.str.2020.11.004Licence: CC BY

Final Published VersionFinal published version, 4.9 MBLicence: CC BY

Cite this

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title = "Dimeric structure of the pseudokinase IRAK3 suggests an allosteric mechanism for negative regulation",

abstract = "Interleukin-1 receptor associated kinases (IRAKs) are key players in innate immune signaling that mediate the host response to pathogens. In contrast to the active kinases IRAK1 and IRAK4, IRAK2 and IRAK3 are pseudokinases lacking catalytic activity and their functions are poorly understood. IRAK3 is thought to be a negative regulator of innate immune signaling and mutations in IRAK3 are associated with asthma and cancer. Here, we report the crystal structure of the human IRAK3 pseudokinase domain in a closed, pseudoactive conformation. IRAK3 dimerizes in a unique way through a head-to-head arrangement not observed in any other kinases. Multiple conserved cysteine residues imply a potential redox control of IRAK3 conformation and dimerization. By analyzing asthma-associated mutations, we identify an evolutionarily conserved surface on IRAK3 that could form an interaction interface with IRAK4, suggesting a model for the negative regulation of IRAK4 by IRAK3.",

keywords = "IRAK kinases, Myddosome, Toll-like/Interleukin-1 receptor signalling, asthma, innate immunity, kinase, kinase inhibitors, protein phosphorylation, pseudoenzymes, signal transduction",

author = "Sven Lange and Nelen, {Marina I.} and Philip Cohen and Yogesh Kulathu",

note = "Funding Information: We thank Matthew McFarland, Stephen Matthews, and Alexia Kalogeropulou for critical reading of the manuscript and helpful comments. We acknowledge MRC Reagents and Services for providing valuable reagents, especially Nicola Wood and Mark Peggie for cloning the constructs used in this study. We are grateful to Danielle Peeters (Janssen Pharmaceutica) and JSC Arthur (University of Dundee) for valuable discussions and to JSC Arthur for sharing proteomic data. We thank the beamline staff at the Diamond Light Source for assistance during diffraction experiments. SML received support from Medical Research Scotland and Janssen Pharmaceutica (PhD-770-2014). PC is supported by MRC grant MR/R021406/1 and YK by MRC grant MC_UU_00018/3, the EMBO Young Investigator Program and the Lister Institute of Preventive Medicine. PC and MIN conceived the study. SML produced proteins, conducted experiments, and analyzed data. MIN, YK and PC supervised the study. SML, YK and PC designed experiments and wrote the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 The Authors Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2021",

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doi = "10.1016/j.str.2020.11.004",

language = "English",

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AU - Lange, Sven

AU - Nelen, Marina I.

AU - Cohen, Philip

AU - Kulathu, Yogesh

N1 - Funding Information: We thank Matthew McFarland, Stephen Matthews, and Alexia Kalogeropulou for critical reading of the manuscript and helpful comments. We acknowledge MRC Reagents and Services for providing valuable reagents, especially Nicola Wood and Mark Peggie for cloning the constructs used in this study. We are grateful to Danielle Peeters (Janssen Pharmaceutica) and JSC Arthur (University of Dundee) for valuable discussions and to JSC Arthur for sharing proteomic data. We thank the beamline staff at the Diamond Light Source for assistance during diffraction experiments. SML received support from Medical Research Scotland and Janssen Pharmaceutica (PhD-770-2014). PC is supported by MRC grant MR/R021406/1 and YK by MRC grant MC_UU_00018/3, the EMBO Young Investigator Program and the Lister Institute of Preventive Medicine. PC and MIN conceived the study. SML produced proteins, conducted experiments, and analyzed data. MIN, YK and PC supervised the study. SML, YK and PC designed experiments and wrote the manuscript. The authors declare no competing interests. Publisher Copyright: © 2020 The Authors Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

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N2 - Interleukin-1 receptor associated kinases (IRAKs) are key players in innate immune signaling that mediate the host response to pathogens. In contrast to the active kinases IRAK1 and IRAK4, IRAK2 and IRAK3 are pseudokinases lacking catalytic activity and their functions are poorly understood. IRAK3 is thought to be a negative regulator of innate immune signaling and mutations in IRAK3 are associated with asthma and cancer. Here, we report the crystal structure of the human IRAK3 pseudokinase domain in a closed, pseudoactive conformation. IRAK3 dimerizes in a unique way through a head-to-head arrangement not observed in any other kinases. Multiple conserved cysteine residues imply a potential redox control of IRAK3 conformation and dimerization. By analyzing asthma-associated mutations, we identify an evolutionarily conserved surface on IRAK3 that could form an interaction interface with IRAK4, suggesting a model for the negative regulation of IRAK4 by IRAK3.

AB - Interleukin-1 receptor associated kinases (IRAKs) are key players in innate immune signaling that mediate the host response to pathogens. In contrast to the active kinases IRAK1 and IRAK4, IRAK2 and IRAK3 are pseudokinases lacking catalytic activity and their functions are poorly understood. IRAK3 is thought to be a negative regulator of innate immune signaling and mutations in IRAK3 are associated with asthma and cancer. Here, we report the crystal structure of the human IRAK3 pseudokinase domain in a closed, pseudoactive conformation. IRAK3 dimerizes in a unique way through a head-to-head arrangement not observed in any other kinases. Multiple conserved cysteine residues imply a potential redox control of IRAK3 conformation and dimerization. By analyzing asthma-associated mutations, we identify an evolutionarily conserved surface on IRAK3 that could form an interaction interface with IRAK4, suggesting a model for the negative regulation of IRAK4 by IRAK3.

KW - IRAK kinases

KW - Myddosome

KW - Toll-like/Interleukin-1 receptor signalling

KW - asthma

KW - innate immunity

KW - kinase

KW - kinase inhibitors

KW - protein phosphorylation

KW - pseudoenzymes

KW - signal transduction

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U2 - 10.1016/j.str.2020.11.004

DO - 10.1016/j.str.2020.11.004

M3 - Article

C2 - 33238146

SN - 0969-2126

VL - 29

SP - 238-251.e4

JO - Structure

JF - Structure

IS - 3

ER -

Dimeric structure of the pseudokinase IRAK3 suggests an allosteric mechanism for negative regulation

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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Elucidation of Mechanisms that Restrict Activation of the Innate Immune System to Prevent Inflammatory and Autoimmune Diseases

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Dimeric structure of the pseudokinase IRAK3 suggests an allosteric mechanism for negative regulation

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

Elucidation of Mechanisms that Restrict Activation of the Innate Immune System to Prevent Inflammatory and Autoimmune Diseases

Cite this