Cutting edge: molecular structure of the IL-1R-associated kinase-4 death domain and its implications for TLR signaling.
IL-1R-associated kinase (IRAK) 4 is an essential component of innate immunity. IRAK-4 deficiency in mice and humans results in severe impairment of IL-1 and TLR signaling. We have solved the crystal structure for the death domain of Mus musculus IRAK-4 to 1.7 A resolution. This is the first glimpse of the structural details of a mammalian IRAK family member. The crystal structure reveals a six-helical bundle with a prominent loop, which among IRAKs and Pelle, a Drosophila homologue, is unique to IRAK-4. This highly structured loop contained between helices two and three, comprises an 11-aa stretch. Although innate immune domain recognition is thought to be very similar between Drosophila and mammals, this structural component points to a drastic difference. This structure can be used as a framework for future mutation and deletion studies and potential drug design.
Lasker
Michael V
MV
Department of Biochemistry, University of Illinois, Urbana 61801, USA.
Gajjar
Mark M
MM
Nair
Satish K
SK
D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D029721:Drosophila Proteins / Q000737:chemistry; D053592:Interleukin-1 Receptor-Associated Kinases; D051379:Mice; D008969:Molecular Sequence Data; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology*; D040681:Structural Homology, Protein
D029721:Drosophila Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C079896:pll protein, Drosophila; D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse; D017346:Protein Serine-Threonine Kinases