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J. Biol. Chem., Vol. 280, Issue 46, 38648-38656, November 18, 2005

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Identification of the Critical Residues Involved in Peptidoglycan Detection by Nod1^*

Stephen E. Girardin12, Muguette Jéhanno¶1, Dominique Mengin-Lecreulx||, Philippe J. Sansonetti, Pedro M. Alzari**, and Dana J. Philpott¶1

From the Unité de Pathogénie Microbienne Moléculaire, INSERM U389, Groupe Inserm Avenir "Peptidoglycan and Innate Immunity," ^¶Groupe Immunité Innée et Signalisation, ^**Unité de Biochimie Structurale, Institut Pasteur, 28 Rue du Dr. Roux, 75724 Paris Cedex 15, France and the ^||Enveloppes Bactériennes et Antibiotiques, IBBMC, UMR 8619 CNRS, Université Paris-Sud, Bât. 430, 91405 Orsay, France

Nod1 is an intracellular pattern recognition molecule activated following bacterial infection, which senses a specific muropeptide (L-Ala-D-Glu-meso-DAP (diaminopimelic acid); "Tri_DAP") from peptidoglycan. Here we investigated the molecular basis of Tri_DAP sensing by human (h) Nod1. Our results identified the domain responsible for Tri_DAP detection in the center of the concave surface of hNod1 leucine-rich repeat domain. Amino acid residues critical for sensing define a contiguous surface patch that is largely conserved in Nod1 proteins from different species. Accordingly, the distinct specificities of human versus murine Nod1 toward muropeptide detection were also found to lie in this central cleft. Several splicing variants of Nod1 lacking repeats 7-9 have been characterized recently, the relative balance of which is thought to correlate with the onset of asthma or inflammatory bowel disease. We demonstrated that these isoforms failed to transduce NF-B activation upon muropeptide stimulation. This study provided insights into the molecular mechanisms responsible for the detection of bacterial peptidoglycan by Nod1 and suggested that defects in Nod1-dependent peptidoglycan sensing may contribute to elicit certain inflammatory disorders.

Received for publication, August 30, 2005 , and in revised form, September 16, 2005.

^* This work was supported by "Programme Transversal de Recheche" Grant 94 from the Pasteur Institute, ACI Microbiologie grant (Inserm, France), Biotox Program (Inserm, France), and "Avenir" Program (Inserm, France) (to S. E. G.). 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.

The on-line version of this article (available at http://www.jbc.org) contains Fig. S1.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Institut Pasteur, 28 Rue du Dr. Roux, 75724 Paris, France. Tel.: 33-1-40-61-37-71; Fax: 33-1-45-68-89-53; E-mail: girardin{at}pasteur.fr.

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