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)

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
19 Downloads (Pure)

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 languageEnglish
Pages (from-to)238-251.e4
Number of pages14
JournalStructure
Volume29
Issue number3
Early online date24 Nov 2020
DOIs
Publication statusPublished - 4 Mar 2021

Keywords

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

Fingerprint Dive into the research topics of 'Dimeric structure of the pseudokinase IRAK3 suggests an allosteric mechanism for negative regulation'. Together they form a unique fingerprint.

Cite this