Article
- The EMBO Journal (2004) 23, 1587 - 1597
- doi:10.1038/sj.emboj.7600175
Published online: 25 March 2004
Subject Categories:
Regulatory regions and critical residues of NOD2 involved in muramyl dipeptide recognition
Tsuyoshi Tanabe1,6,7, Mathias Chamaillard1,7, Yasunori Ogura1, Li Zhu1, Su Qiu1, Junya Masumoto1, Partho Ghosh2, Anthony Moran3, Martina M Predergast3, Gerard Tromp4, Charlene J Williams5, Naohiro Inohara1,8 and Gabriel Núñez1,8
- Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA
- Department of Microbiology, National University of Ireland, Galway, Ireland
- Wayne State University School of Medicine, Detroit, MI, USA
- Department of Medicine, Division of Rheumatology, Thomas Jefferson University, Philadelphia, PA, USA
- Current address: The Gene Discovery Research Center, The National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki 305-8562, Japan
- These authors share first authorship
- These authors share senior authorship
Correspondence to:
Gabriel Núñez, Department of Pathology, University of Michigan Medical School, 4219 CCGC 0938, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0938, USA. Tel.: +1 734 764 8514; Fax: +1 734 647 9654; E-mail: bclx@med.umich.edu
Received 11 November 2003; Accepted 27 February 2004
Abstract
Multiple genetic variants of CARD15/NOD2 have been associated with susceptibility to Crohn's disease and Blau syndrome. NOD2 recognizes muramyl dipeptide (MDP) derived from bacterial peptidoglycan (PGN), but the molecular basis of recognition remains elusive. We performed systematic mutational analysis to gain insights into the function of NOD2 and molecular mechanisms of disease susceptibility. Using an archive of 519 mutations covering 
50% of the amino-acid residues of NOD2, the essential regulatory domains and specific residues of NOD2 involved in recognition of MDP were identified. The analysis revealed distinct roles for N-terminal and C-terminal leucine-rich repeats (LRRs) in the modulation of NOD2 activation and bacterial recognition. Within the C-terminal LRRs, variable residues predicted to form the 
-strand/turn structure were found to be essential for the response to MDP. In addition, we analyzed NOD1, a NOD2-related protein, revealing conserved and nonconserved amino-acid residues involved in PGN recognition. These results provide new insights into the molecular function and regulation of NOD2 and related NOD family proteins.
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