TY - JOUR
T1 - Regulatory regions and critical residues of NOD2 involved in muramyl dipeptide recognition
AU - Tanabe, Tsuyoshi
AU - Chamaillard, Mathias
AU - Ogura, Yasunori
AU - Zhu, Li
AU - Qiu, Su
AU - Masumoto, Junya
AU - Ghosh, Partho
AU - Moran, Anthony
AU - Predergast, Martina M.
AU - Tromp, Gerard
AU - Williams, Charlene J.
AU - Inohara, Naohiro
AU - Núñez, Gabriel
PY - 2004/4/7
Y1 - 2004/4/7
N2 - 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 βstrand/βturn 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.
AB - 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 βstrand/βturn 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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U2 - 10.1038/sj.emboj.7600175
DO - 10.1038/sj.emboj.7600175
M3 - Article
C2 - 15044951
AN - SCOPUS:2342583513
SN - 0261-4189
VL - 23
SP - 1587
EP - 1597
JO - EMBO Journal
JF - EMBO Journal
IS - 7
ER -