title: Blau syndrome polymorphisms in NOD2 identify nucleotide hydrolysis and helical domain 1 as signalling regulators.
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/Mg(2+)-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.
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, UK.
authors.forename: Rhiannon
authors.initials: R
authors.lastname: Parkhouse
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, UK; Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Boyle
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, UK; Department of Veterinary Medicine, University of Cambridge, Cambridge, UK. Electronic address: tpm22@cam.ac.uk.
authors.forename: Tom P
authors.initials: TP
authors.lastname: Monie
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001168:Arthritis; D003389:Cranial Nerve Diseases / Q000201:enzymology / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D006868:Hydrolysis; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000502:physiology; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D012507:Sarcoidosis; D015398:Signal Transduction; D013585:Synovitis / Q000201:enzymology / Q000235:genetics*; D014605:Uveitis / Q000201:enzymology / Q000235:genetics*; D056660:Hereditary Autoinflammatory Diseases
chemical_list: D016328:NF-kappa B; C119067:NOD1 protein, human; C429018:NOD2 protein, human; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein
keywords: Blau syndrome; Innate immunity; NACHT; Nucleotide oligomerisation domain containing 2; Nucleotide-binding, leucine-rich repeat containing receptor; Single nucleotide polymorphisms
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