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Blau syndrome polymorphisms in NOD2 identify nucleotide hydrolysis and helical domain 1 as signalling regulators |
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| Authors: | Rhiannon Parkhouse Joseph P Boyle Tom P Monie |
| Institution: | 1. Department of Biochemistry, University of Cambridge, Cambridge, UK;2. Department of Veterinary Medicine, University of Cambridge, Cambridge, UK |
| Abstract: | Understanding how single nucleotide polymorphisms (SNPs) lead to disease at a molecular level provides a starting point for improved therapeutic intervention. SNPs in the innate immune receptor nucleotide oligomerisation domain 2 (NOD2) can cause the inflammatory disorders Blau Syndrome (BS) and early onset sarcoidosis (EOS) through receptor hyperactivation. Here, we show that these polymorphisms cluster into two primary locations: the ATP/Mg2+-binding site and helical domain 1. Polymorphisms in these two locations may consequently dysregulate ATP hydrolysis and NOD2 autoinhibition, respectively. Complementary mutations in NOD1 did not mirror the NOD2 phenotype, which indicates that NOD1 and NOD2 are activated and regulated by distinct methods. |
| Keywords: | BS Blau syndrome CAPS cryopyrin-associated periodic syndromes EOS early onset sarcoidosis HD helical domain NACHT found in NAIP CIITA HET-E and TP-1 NF-κB nuclear factor kappa B NLR nucleotide-binding leucine-rich repeat containing receptor NOD nucleotide oligomerisation domain RIP2 receptor interacting protein 2 SNP single nucleotide polymorphism |
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