Defective IRAK4 does not bind MyD88 within the TLR2/4 complex

Stable Identifier
Reaction [transition]
Homo sapiens
Related Species
Chlamydia trachomatis, Neisseria meningitidis serogroup B
Locations in the PathwayBrowser
SVG |   | PPTX  | SBGN
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout
Autosomal recessive IRAK-4 deficiency leads to impaired TLR responses in leukocytes and is associated with increased susceptibility to pyogenic bacterial infections in childhood (Picard C et al. 2003; Medvedev AE et al. 2003; Yamamoto T et al. 2014). Unlike most of the identified gene variants of IRAK4 with nonsense or frame shift mutations that create premature stop codons and result in abolished IRAK4 production, the protein level of missence variant IRAK4 R12C was comparable with wild type (WT) when expressed in human embryonic kidney 293 (HEK293T) cells (Ku CL et al. 2007; Yamamoto T et al. 2014). Analytical gel filtration of recombinant WT or mutant IRAK4 and MyD88 proteins revealed that IRAK4 R12C failed to form a complex with MyD88. These results are in agreement with nuclear magnetic resonance (NMR) titration study that showed a lower affinity of IRAK R12C variant towards 1H-15N-labeled MyD88 N-terminal domain (Yamamoto T et al. 2014).
Literature References
PubMed ID Title Journal Year
24316379 Functional assessment of the mutational effects of human IRAK4 and MyD88 genes

Kondo, N, Shirakawa, M, Ohnishi, H, Tochio, H, Kato, Z, Tsutsumi, N, Kubota, K, Yamamoto, T

Mol. Immunol. 2014
17878374 TLR9 activation induces normal neutrophil responses in a child with IRAK-4 deficiency: involvement of the direct PI3K pathway

Lebranchu, Y, François, S, Hoarau, C, Gougerot-Pocidalo, MA, El Benna, J, Dang, PM, Lescanne, E, Grandchamp, B, Gérard, B, Elbim, C, Lacapère, JJ, Henry, D

J. Immunol. 2007
Normal reaction
Functional status

Loss of function of IRAK4 R12C [cytosol]

Name Identifier Synonyms
primary immunodeficiency disease DOID:612 immune deficiency disorder, immunodeficiency syndrome, hypoimmunity
Cite Us!