Regulatory regions and critical residues of NOD2 involved in muramyl dipeptide recognition
Open Access
- 25 March 2004
- journal article
- research article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 23 (7), 1587-1597
- https://doi.org/10.1038/sj.emboj.7600175
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 β‐strand/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.Keywords
This publication has 38 references indexed in Scilit:
- An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acidNature Immunology, 2003
- NODs: intracellular proteins involved in inflammation and apoptosisNature Reviews Immunology, 2003
- Nod2 Is a General Sensor of Peptidoglycan through Muramyl Dipeptide (MDP) DetectionJournal of Biological Chemistry, 2003
- Host Recognition of Bacterial Muramyl Dipeptide Mediated through NOD2Journal of Biological Chemistry, 2003
- Intracellular vs extracellular recognition of pathogens – common concepts in mammals and fliesTrends in Microbiology, 2002
- RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systemsNature, 2002
- Plant pathogens and integrated defence responses to infectionNature, 2001
- Nod2, a Nod1/Apaf-1 Family Member That Is Restricted to Monocytes and Activates NF-κBJournal of Biological Chemistry, 2001
- Human Nod1 Confers Responsiveness to Bacterial LipopolysaccharidesPublished by Elsevier BV ,2001
- Nod1, an Apaf-1-like Activator of Caspase-9 and Nuclear Factor-κBPublished by Elsevier BV ,1999