title: Enhancement of Muramyl Dipeptide-Dependent NOD2 Activity by a Self-Derived Peptide.
abstract: Nucleotide-binding and oligomerization domain like receptors (NLR) are pattern recognition receptors used to provide rapid immune response by detecting intracellular pathogen-associated molecules. Loss of NLR activity is implicated in genetic disorders, disruption of adaptive immunity, and chronic inflammation. One NLR protein, NOD2, is frequently mutated in Crohn's disease (CD), which is an inflammatory disease of the gastrointestinal tract. Three commonly occurring CD-associated NOD2 mutations, R702W, G908R, and L1007fs, are clustered near the regulatory domain, leucine rich region (LRR), and lowers the activity of NOD2 in response to muramyl dipeptide (MDP). As LRR is also the ligand binding domain, this suggests that the mutations either affect the binding of MDP or how the molecule responds to ligand binding. To model the role of R702 in ligand-dependent activation of NOD2, we used homology modeling to map the residue R702 to the interface between the oligomerization domain and LRR. We show that a peptide derived from NOD2(697-718) binds LRR in vitro, and upon co-expressing or importing the peptide into HEK293 expressing NOD2, there is an increase in the MDP-dependent NOD2 activity. The study thus suggests that the R702W mutation interferes with the conformational changes needed for MDP binding and activation. J. Cell. Biochem. 118: 1227-1238, 2017. © 2016 Wiley Periodicals, Inc.
authors: Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, New York, 14260.
authors: Jasdeep K
authors: JK
authors: Mann
authors: Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, New York, 14260.
authors: Jiaochen
authors: J
authors: Shen
authors: Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, New York, 14260.
authors: Sheldon
authors: S
authors: Park
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology*; D003424:Crohn Disease / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D011487:Protein Conformation; D000072417:Protein Domains; D040681:Structural Homology, Protein
chemical_list: C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D010455:Peptides; D000119:Acetylmuramyl-Alanyl-Isoglutamine
keywords: AUTOINHIBITION; CROHN'S DISEASE; MECHANISM OF ACTIVATION; NOD2; PEPTIDE LIGAND