IRAK4 Dimerization and trans -Autophosphorylation Are Induced by Myddosome Assembly

Ferrao, Ryan; Zhou, Hao; Shan, Yibing; Liu, Qun; Li, Qiubai; Shaw, David E.; Li, Xiaoxia; Wu, Hao

doi:10.1016/j.molcel.2014.08.006

Cited by 120 publications

(168 citation statements)

References 41 publications

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“…On the other hand, oligomerization of effector enzymes, such as kinases and caspases, enhances the allosteric changes that are presumed to be required for enzyme activation. This oligomerization-facilitated allostery is illustrated by the recently reported crystal structure of the unphosphorylated IRAK4 kinase domain asymmetric dimer captured in the conformation of the Myddosome-induced IRAK4 trans -autophosphorylation reaction 34 . In the crystal structure, one IRAK4 monomer exists in the active kinase conformation despite a lack of phosphorylation and it precisely binds the activation loop phosphosite of the other IRAK4 monomer for phospho-transfer.…”

Section: Smocs For Prrsmentioning

confidence: 90%

SMOCs: supramolecular organizing centres that control innate immunity

2014

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The diverse receptor families of the innate immune system activate signal transduction pathways that are important for host defence, but common themes to explain the operation of these pathways remain undefined. In this Opinion article, we propose — on the basis of recent structural and cell biological studies — the concept of supramolecular organizing centres (SMOCs) as location-specific higher-order signalling complexes in which increased local concentrations of signalling components promote the intrinsically weak allosteric interactions that are required for enzyme activation. We suggest that SMOCs are assembled on various membrane-bound organelles or other intracellular sites, which may assist signal amplification to reach a response threshold and potentially define the specificity of cellular responses that are induced in response to infectious and non-infectious insults.

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Section: Smocs For Prrsmentioning

confidence: 90%

SMOCs: supramolecular organizing centres that control innate immunity

2014

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“…Oligomerization-induced autophosphorylation of IRAK4 must execute through allosteric changes that are only possible at a high local concentration. The recent crystal structure of the IRAK4 kinase domain (KD) containing an active site mutation showed an asymmetric dimer structure caught in the act of trans -autophosphorylation (54). Despite being unphosphorylated, one IRAK4 KD molecule (the “enzyme”) is in the active conformation, whereas the other IRAK4 KD molecule (“substrate”) shows a protruded activation loop.…”

Section: The Toll-like Receptor/il-1r Signaling Pathwaymentioning

confidence: 99%

“…The enzyme IRAK4 active site precisely accepts the cognate phosphorylation residue T345 from the substrate for trans -autophosphorylation (Figure 3 f ). Further biochemical and cellular studies show that the observed dimerization interface is vital for IRAK4 autophosphorylation and signal transduction (54). Small- and wide-angle X-ray scattering (SAXS/WAXS) of full-length (FL) IRAK4 in complex with MyD88 DD reveals a central core with two flanking lobes, suggesting a MyD88/IRAK4 DD complex core at the center and two IRAK4 KD dimers at the periphery (Figure 3 g ).…”

Section: The Toll-like Receptor/il-1r Signaling Pathwaymentioning

confidence: 99%

Structural Biology of Innate Immunity

Yin

et al. 2015

Annu. Rev. Immunol.

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Innate immune responses depend on timely recognition of pathogenic or danger signals by multiple cell surface or cytoplasmic receptors and transmission of signals for proper counteractions through adaptor and effector molecules. At the forefront of innate immunity are four major signaling pathways, including those elicited by Toll-like receptors, RIG-I-like receptors, inflammasomes, or cGAS, each with its own cellular localization, ligand specificity, and signal relay mechanism. They collectively engage a number of overlapping signaling outcomes, such as NF-κB activation, interferon response, cytokine maturation, and cell death. Several proteins often assemble into a supramolecular complex to enable signal transduction and amplification. In this article, we review the recent progress in mechanistic delineation of proteins in these pathways, their structural features, modes of ligand recognition, conformational changes, and homo- and hetero-oligomeric interactions within the supramolecular complexes. Regardless of seemingly distinct interactions and mechanisms, the recurring themes appear to consist of autoinhibited resting-state receptors, ligand-induced conformational changes, and higher-order assemblies of activated receptors, adaptors, and signaling enzymes through conserved protein-protein interactions.

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“…Several kinase structures have been reported in which a serine, threonine, or tyrosine autophosphorylation site of one kinase monomer is present in the active site of another monomer of the same protein in the crystal (7-15). In these structures, the position of the phosphorylation site and adjacent residues resembles those of substrates in structures of substrate peptides bound to kinases (16-18).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, each of these residues is an experimentally verified autophosphorylation site in these kinases. For serine/threonine kinases, autophosphorylation complexes of the activation loop Thr residues of p21-activated kinase (PAK1) [PDB: 3Q4Z (11)] and interleukin-1 receptor-associated kinase 4 (IRAK4) [PDB: 4U97; PDB: 4U9A (15)] have been described, as have autophosphorylation complexes of the C-terminal regulatory regions of human [PDB: 2WEL (12)] and Caenorhabditis elegans [PDB: 3KK8; PDB: 3KK9 (13)] calcium/calmodulin-dependent kinase II (CaMKII).…”

Section: Introductionmentioning

confidence: 99%

Identifying three-dimensional structures of autophosphorylation complexes in crystals of protein kinases

Malecka

Fink

et al. 2015

Sci. Signal.

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Protein kinase autophosphorylation is a common regulatory mechanism in cell signaling pathways. Crystal structures of several homomeric protein kinase complexes have a serine, threonine, or tyrosine autophosphorylation site of one kinase monomer located in the active site of another monomer, a structural complex that we call an “autophosphorylation complex.” We developed and applied a structural bioinformatics method to identify all such autophosphorylation kinase complexes in X-ray crystallographic structures in the Protein Data Bank (PDB). We identified 15 autophosphorylation complexes in the PDB, of which 5 complexes had not previously been described in the publications describing the crystal structures. These 5 consist of tyrosine residues in the N-terminal juxtamembrane regions of colony stimulating factor 1 receptor (CSF1R, Tyr561) and EPH receptor A2 (EPHA2, Tyr594), tyrosine residues in the activation loops of the SRC kinase family member LCK (Tyr394) and insulin-like growth factor 1 receptor (IGF1R, Tyr1166), and a serine in a nuclear localization signal region of CDC-like kinase 2 (CLK2, Ser142). Mutations in the complex interface may alter autophosphorylation activity and contribute to disease; therefore we mutated residues in the autophosphorylation complex interface of LCK and found that two mutations impaired autophosphorylation (T445V and N446A) and mutation of Pro447 to Ala, Gly, or Leu increased autophosphorylation. The identified autophosphorylation sites are conserved in many kinases, suggesting that, by homology, these complexes may provide insight into autophosphorylation complex interfaces of kinases that are relevant drug targets.

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IRAK4 Dimerization and trans -Autophosphorylation Are Induced by Myddosome Assembly

Cited by 120 publications

References 41 publications

SMOCs: supramolecular organizing centres that control innate immunity

SMOCs: supramolecular organizing centres that control innate immunity

Structural Biology of Innate Immunity

Identifying three-dimensional structures of autophosphorylation complexes in crystals of protein kinases

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