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].