title: Systemic lupus erythematosus-associated neutrophil cytosolic factor 2 mutation affects the structure of NADPH oxidase complex.
abstract: In a case-control association study with 3716 North Americans of Hispanic descent and 4867 North Americans of European descent, we show that the associations of rs17849502 (NCF2 His-389 → Gln) and rs13306575 (NCF2 Arg-395 → Trp) with systemic lupus erythematosus are independent. We have shown that His-389 → Gln disrupts the binding of NCF2 to the ZF domain of VAV1, resulting in decreased NADPH oxidase activity. With respect to Arg-395 → Trp, using protein docking and structure analyses, we provide a model for the involvement of this mutation in the structure and function of the NADPH oxidase complex. This model assigns a central role to Arg-395 in the structure and stability of the quaternary NCF2/NCF4/VAV1/RAC1 NADPH oxidase complex. Arg-395 stabilizes the C-terminal tail of NCF4 and the conformation of NCF2 loop 395-402, which in turn stabilize the evolutionarily conserved interactions of NCF2/NCF4 with the DH domain of VAV1 and RAC1 region 120-137. Our findings are consistent with the high levels of conservation of all of the residues involved in these interactions.
authors: From the Lupus Genetic Group, Department of Medicine, University of Southern California, Los Angeles, California 90089.
authors: Don L
authors: DL
authors: Armstrong
authors: the Department of Chemical Research Support, Weizmann Institute of Science, Rehovot 76100, Israel.
authors: Miriam
authors: M
authors: Eisenstein
authors: From the Lupus Genetic Group, Department of Medicine, University of Southern California, Los Angeles, California 90089, the Cell Biology and Neuroscience, University of California, Riverside, California 92521, and.
authors: Raphael
authors: R
authors: Zidovetzki
authors: From the Lupus Genetic Group, Department of Medicine, University of Southern California, Los Angeles, California 90089, jacob@usc.edu.
authors: Chaim O
authors: CO
authors: Jacob
mesh_terms: D019943:Amino Acid Substitution; D004795:Enzyme Stability / Q000235:genetics; D005260:Female; D006630:Hispanic or Latino; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D008297:Male; D062105:Molecular Docking Simulation; D020125:Mutation, Missense; D019255:NADPH Oxidases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D051567:Proto-Oncogene Proteins c-vav / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D044465:White People; D020830:rac1 GTP-Binding Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D010750:Phosphoproteins; D051567:Proto-Oncogene Proteins c-vav; C107953:RAC1 protein, human; C496618:VAV1 protein, human; C085072:neutrophil cytosol factor 40K; D019255:NADPH Oxidases; C527764:NCF2 protein, human; C113333:NCF4 protein, human; D020830:rac1 GTP-Binding Protein
keywords: NADPH oxidase; NCF2; autoimmune disease; autoimmunity; computational biology; human genetics; systemic lupus erythematosus