Systemic lupus erythematosus-associated neutrophil cytosolic factor 2 mutation affects the structure of NADPH oxidase complex.
J Biol Chem
; 290(20): 12595-602, 2015 May 15.
Article
em En
| MEDLINE
| ID: mdl-25795782
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 â Gln) and rs13306575 (NCF2 Arg-395 â Trp) with systemic lupus erythematosus are independent. We have shown that His-389 â Gln disrupts the binding of NCF2 to the ZF domain of VAV1, resulting in decreased NADPH oxidase activity. With respect to Arg-395 â 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.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
NADPH Oxidases
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Mutação de Sentido Incorreto
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Simulação de Acoplamento Molecular
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Lúpus Eritematoso Sistêmico
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Limite:
Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article