Engineered peptide to restore NOD2 response to bacterial peptidoglycan
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Mutations in the Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) are associated with several inflammatory diseases, including Crohn's disease (CD). The CD associated mutations of NOD2 lower its response to intracellular bacterial ligand muramyl dipeptide (MDP), a derivative of peptidoglycan, suggesting that the loss of NOD2 signaling may contribute to the disease pathogenesis. Since the activation of NOD2 is thought to be autoinhibited through interactions involving the ligand binding domain Leucine rich repeats (LRR) to prevent its activation in the absence of a ligand, we used molecular modeling to identify the NOD2 residues 697-718 form a helix that are involved in interdomain interaction with LRR. We showed that a peptide derived from the helix can compete with autoinhibitory interaction and thereby increase its activity in the cell. We showed that co-expressing the peptide, α6, or introducing synthetic peptide α6 in NOD2-expressing HEK293T increased the MDP dependent activation of NOD2. Thus focusing on targeting the peptide(α6)-LRR interaction with an engineered molecule which enhance the activation of NOD2 may be useful to treat the diseases caused by loss of function mutations in the NOD2 gene.