Abstract
Amino acids with functional or key structural roles display higher degrees of conservation through evolution. The comparative analysis of protein sequences from multiple species and/or between homologous proteins can be highly informative in the identification of key structural and functional residues. Residues which in turn provide insight into the molecular mechanisms of protein function. We have explored the genomic and amino acid conservation of the prototypic innate immune genes NOD1 and NOD2. NOD1 orthologs were found in all vertebrate species analyzed, whilst NOD2 was absent from the genomes of avian, reptilian and amphibian species. Evolutionary trace analysis was used to identify highly conserved regions of NOD1 and NOD2 across multiple species. Consistent with the known functions of NOD1 and NOD2 highly conserved patches were identified that matched the Walker A and B motifs and provided interaction surfaces for the adaptor protein RIP2. Other patches of high conservation reflect key structural functions as predicted by homology models. In addition, the pattern of residue conservation within the leucine-rich repeat (LRR) region of NOD1 and NOD2 is indicative of a conserved mechanism of ligand recognition involving the concave surface of the LRRs.
Highlights
NOD1 and NOD2 are prototypical members of the NLR family of cytosolic pattern recognition receptors and the human and murine proteins have been widely studied
Exposure to ligand results in conformational rearrangement that permits receptor self-association and nucleotide binding via highly conserved amino acid motifs in the central NOD region [7]. This is coupled with migration to the plasma membrane and caspase activation and recruitment domain (CARD) mediated interaction with the adaptor protein RIP2 and/or CARD9
We found that regions of NOD1 and NOD2 already reported to provide essential functional roles showed increased, or even complete, conservation across species
Summary
NOD1 and NOD2 are prototypical members of the NLR family of cytosolic pattern recognition receptors and the human and murine proteins have been widely studied. Exposure to ligand results in conformational rearrangement that permits receptor self-association and nucleotide binding via highly conserved amino acid motifs in the central NOD (or NACHT) region [7]. This is coupled with migration to the plasma membrane and caspase activation and recruitment domain (CARD) mediated interaction with the adaptor protein RIP2 and/or CARD9. The net effect is to initiate a pro-inflammatory response mediated by NFκB and stress-kinase activated genes
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