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Proc Natl Acad Sci U S A. 2017 Dec 19;114(51):13507-13512. doi: 10.1073/pnas.1714386114. Epub 2017 Dec 5.

Crystal structure of human IRAK1.

Wang L1,2, Qiao Q1,2, Ferrao R1,2, Shen C1,2, Hatcher JM1,3, Buhrlage SJ1,3, Gray NS1,3, Wu H4,2.

Author information

1
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.
2
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.
3
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115.
4
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115; wu@crystal.harvard.edu.

Abstract

Interleukin 1 (IL-1) receptor-associated kinases (IRAKs) are serine/threonine kinases that play critical roles in initiating innate immune responses against foreign pathogens and other types of dangers through their role in Toll-like receptor (TLR) and interleukin 1 receptor (IL-1R) mediated signaling pathways. Upon ligand binding, TLRs and IL-1Rs recruit adaptor proteins, such as myeloid differentiation primary response gene 88 (MyD88), to the membrane, which in turn recruit IRAKs via the death domains in these proteins to form the Myddosome complex, leading to IRAK kinase activation. Despite their biological and clinical significance, only the IRAK4 kinase domain structure has been determined among the four IRAK family members. Here, we report the crystal structure of the human IRAK1 kinase domain in complex with a small molecule inhibitor. The structure reveals both similarities and differences between IRAK1 and IRAK4 and is suggestive of approaches to develop IRAK1- or IRAK4-specific inhibitors for potential therapeutic applications. While the IRAK4 kinase domain is capable of homodimerization in the unphosphorylated state, we found that the IRAK1 kinase domain is constitutively monomeric regardless of its phosphorylation state. Additionally, the IRAK1 kinase domain forms heterodimers with the phosphorylated, but not unphosphorylated, IRAK4 kinase domain. Collectively, these data indicate a two-step kinase activation process in which the IRAK4 kinase domain first homodimerizes in the Myddosome, leading to its trans-autophosphorylation and activation. The phosphorylated IRAK4 kinase domain then forms heterodimers with the IRAK1 kinase domain within the Myddosome, leading to its subsequent phosphorylation and activation.

KEYWORDS:

IRAK1; crystal structure; interleukin 1 receptor-associated kinases

PMID:
29208712
PMCID:
PMC5754798
DOI:
10.1073/pnas.1714386114
[Indexed for MEDLINE]
Free PMC Article

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