Journal of Leukocyte Biology Myeloid cells, immune suppression, tumor immunology
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Originally published online as doi:10.1189/jlb.0507290 on June 4, 2008

Published online before print June 4, 2008
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(Journal of Leukocyte Biology. 2008;84:807-813.)
© 2008 by Society for Leukocyte Biology

Threonine 66 in the death domain of IRAK-1 is critical for interaction with signaling molecules but is not a target site for autophosphorylation

Detlef Neumann*,1, Christian Kollewe*,2, Andreas Pich{dagger}, Ping Cao{ddagger}, Klaus Resch* and Michael U. Martin*,2

* Departments of Pharmacology and
{dagger} Toxicology, Hannover Medical School, Hannover, Germany; and
{ddagger} Amgen SF, LLC, South San Francisco, California, USA

1 Correspondence: Medizinische Hochschule Hannover, Dept. of Pharmacology OE 5320, Carl-Neuberg-Str.1, D-30625 Hannover, Germany. E-mail: neumann.detlef{at}mh-hannover.de

Ligand binding in the TLR/IL-1R family results in the transient formation of an intracellular signaling complex, which contains, amongst others, the serine/threonine-specific kinase IL-1R-associated kinase 1 (IRAK-1). Concomitantly, the kinase function of IRAK-1 becomes activated, resulting in massive autophosphorylation and finally in the dissociation of the initially constituted signaling complex. The death domain (DD) of IRAK-1 mediates the interaction with other molecules of the signaling complex, e.g., the adaptor MyD88, the silencer Tollip, and the activator kinase IRAK-4. The conserved threonine at position 66 (T66), located within the DD, is a putative autophosphorylation target site. Here, we provide evidence that T66 critically impacts the secondary structure of the IRAK-1 DD. Thereby, it ensures the transient manner of interactions between IRAK-1 and the other signaling molecules. This essential role, however, is not regulated by phosphorylation of T66 itself.

Key Words: inflammation • kinases • interleukin-1 • Toll-like receptor • Tollip






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