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Identification of an N-Terminal Recognition Site in TLR9 That Contributes to CpG-DNA-Mediated Receptor Activation¹

Mirjam E. Peter^2,*, Andriy V. Kubarenko^2,, Alexander N. R. Weber^3, and Alexander H. Dalpke^3,*

^* Department of Medical Microbiology and Hygiene, University Heidelberg, Heidelberg, Germany; and Junior Research Group "Toll-like Receptors and Cancer," German Cancer Research Center, Heidelberg, Germany

Although it is well established that TLR9 recognizes CpG-DNA, the structural details of ligand-receptor interaction are still mostly unknown. The extracellular domain of TLR9 is composed of 25 leucine-rich repeat (LRR) motifs, 5 of which bear inserting sequences that do not conform to the LRR consensus motif. In this study, we show that the functional integrity of the extracellular domain of murine TLR9 is lost by deletion of individual LRR motifs. When deleting only the inserting sequences, we observed that LRR2, 5, and 8 contribute to receptor activation by CpG-DNA. The latter deletions did not affect receptor dimerization but inhibited CpG-DNA binding. On the basis of a homology modeling approach, we furthermore identify a positively charged region in the N terminus that is essential for CpG-DNA-induced TLR9 activation. This interaction site mirrors findings previously shown for the structural recognition of dsRNA by TLR3 and hints toward a general principle of nucleic acid recognition by the respective TLR.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft DA592/3 (to A.H.D.); Emmy Noether program (to A.N.R.W.)) and by the German Cancer Research Center (to A.V.K., A.N.R.W.).

² M.E.P. and A.V.K. contributed equally.

³ Address correspondence and reprint requests to Dr. Alexander H. Dalpke, Department of Medical Microbiology and Hygiene, Hygiene-Institute, University Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany; E-mail address: alexander.dalpke{at}med.uni-heidelberg.de or Dr. Alexander N. R. Weber, Junior Group "Toll-like Receptors and Cancer," German Cancer Research Center, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany. E-mail address: alexander.weber{at}dkfz.de

⁴ Abbreviations used in this paper: ECD, extracellular domain; HA, hemagglutinin; LRR, leucine-rich repeat; ODN, oligodeoxynucleotide; WT, wild type.