2. NOD2 signaling
2.1 Functions of NOD2 domains
NOD2, encoded by the CARD15 gene, consists of 1040 amino acids with a molecular weight of 110 kDa. The expression of NOD2 is observed in hematopoietic cells like macrophages, Dendritic cells (DC), as well as in non-hematopoietic cells like epithelial cells [6]. NOD2 is the sensor of MDP, a PAMP that is ubiquitously present in Gram-negative and positive bacteria[3]. Iyer et al. considered that polymeric PGN is a better pro-inflammatory inducer of NOD2-dependent responses than MDP, although the possibility of contaminants in the polymeric peptidoglycan cannot be completely excluded[7].
The structure of NOD2 protein contains three domains: a leucine-rich repeat (LRR) domain at the carboxy terminal, a nucleotide-binding domain (NBD) in the middle, and two caspase recruitment domains (CARD) at the amino-terminal (Figure 1) . The LRR domain of NOD2 is involved in the recognition of MDP and triggers its protein conformational change[8], thereby contributing to the NBD-mediated oligomerization of NOD proteins[9]. NOD2 variants located in the LRR region (Arg702Trp, Gly908Arg, Leu1007fsinsC) are susceptible to CD[10,11]. While mutations (Arg334Trp, Arg334Gln, Leu469Phe) in the NBD region lead to defective NOD2 oligomerization and cause Blau syndrome[12]. The CARD domain of NOD2 interacts with the CARD of receptor-interacting protein 2 (RIP2), which has been determined at the structural level[13,14].