l-Ala-γ-d-Glu-meso-diaminopimelic Acid (DAP) Interacts Directly with Leucine-rich Region Domain of Nucleotide-binding Oligomerization Domain 1, Increasing Phosphorylation Activity of Receptor-interacting Serine/Threonine-protein Kinase 2 and Its Interaction with Nucleotide-binding Oligomerization Domain 1

Abstract

Commensal bacteria that colonize the human colon produce significant amounts of di/tripeptides. We were the first to report that PepT1 transports the small formylated bacterial peptide (fMLP) (1, 2). In the interval since that time, we have shown that other bacterial peptides, such as MDP 3 and Tri-DAP, may also be transported by hPepT1 (3, 4). Small bacterial peptides occur at substantially lower levels in the small intestine compared with the colon in line with the reduced numbers of prokaryotes present in the small intestine of humans. Interestingly, hPepT1 expression is normally restricted to the small intestine, a site in which the levels of small bacterial peptides are low, reflecting the sparse bacterial load of this tissue relative to that of the colon. Thus, the profile of hPepT1 expression along the normal human digestive tract is such that access of small bacterial peptides to hPepT1 minimizes intracellular uptake of these peptides. This normal expression pattern becomes altered in patients with chronic ulcerative colitis or Crohn disease in whom expression of hPepT1 occurs in the colon. The transporter will consequently mediate the intracellular accumulation of small prokaryotic materials. We and others have shown that such accumulation of bacterial products (including

NOD-Like Receptors: Versatile Cytosolic Sentinels

“…The study concluded that the Salmonella virulence factor SopE alters the activation of the RhoGTPases, Rac1 and Cdc42, which is sensed by NOD1 to induce NF-B-signaling by RIP2 (135). This model is inconsistent with recent studies providing evidence for a direct interaction between NOD1 and its ligand Tri-DAP (155). Future studies in RAC1-and Cdc42-deficient cells should be performed to address the strength of effectordriven immunity by NLRs in these models.…”

NOD-Like Receptors: Guardians of Intestinal Mucosal Barriers

“…In contrast, NOD2 recognizes MDP, a PGN fragment that is found in Gram-negative and Grampositive bacteria alike (34) ( Table 1). The LRR region of NOD1 or NOD2 is essential for PGN detection (33,106), and recent evidence has revealed direct binding of these domains to PGN fragments (37,62,77). It is thought that direct binding of MDP or ieDAP leads to a conformational change of the LRR horseshoe structure and to homodimerization of the NLR via the NOD domain (56, 100).…”

International Union of Basic and Clinical Pharmacology. XCVI. Pattern Recognition Receptors in Health and Disease

“…Recent evidence suggests, albeit with certain caveats, that NOD1 and NOD2 do indeed directly sense their ligands (Monie, 2013). The first evidence of direct interaction was provided using the biophysical techniques atomic force microscopy and surface plasmon resonance to show that ie-DAP bound to immobilized commercially prepared NOD1 but that no interaction was detected between NOD1 and MDP or after removal of the NOD1 LRRs (Laroui et al, 2011). Although this provided some indication of interaction specificity and supported a critical role in ligand recognition for the LRRs of NOD1, a failure of NOD1 to interact with a wider range of small molecules would strengthen the interpretation of the data.…”