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The Journal of Immunology, 2005, 175: 4175-4179.
Copyright © 2005 by The American Association of Immunologists


CUTTING EDGE

Cutting Edge: Molecular Structure of the IL-1R-Associated Kinase-4 Death Domain and Its Implications for TLR Signaling1

Michael V. Lasker*,{dagger}, Mark M. Gajjar* and Satish K. Nair2,*,{ddagger}

* Department of Biochemistry, {dagger} Medical Scholars Program, and {ddagger} Center for Biophysics and Computational Biology, University of Illinois, Urbana-Champaign, Urbana, IL 61801

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 Å 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.




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