Accuri C6 Flow Cytometer System
A more recent version of this article appeared on September 1, 2008

Published online before print June 4, 2008
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0507290

Received for publication May 8, 2007.
Revised March 25, 2008.
Accepted for publication April 18, 2008.

Article

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 *@, Christian Kollewe *, Andreas Pich {dagger}, Ping Cao {ddagger}, Klaus Resch *, and Michael U. Martin *

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

@ To whom correspondence should be addressed. E-mail: Neumann.Detlef{at}MH-Hannover.de.


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Abstract

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