Systemic Lupus Erythematosus-associated Neutrophil Cytosolic Factor 2 mutation affects the structure of the NADPH oxidase complex [Molecular Bases of Disease]

March 20th, 2015 by Armstrong, D. L., Eisenstein, M., Zidovetzki, R., Jacob, C. O.

In a case-control association study with 3716 North Americans of Hispanic descent (HispNA) and 4867 North Americans of European descent (EA), we show that the associations of rs17849502 (NCF2 H389→Q) and rs13306575 (NCF2 R395→W) with Systemic Lupus Erythematosus (SLE) are independent. We have shown that H389→Q dis- rupts the binding of NCF2 to the ZF domain of VAV1, and results in decreased NADPH oxidase activity. With respect to R395→W, 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 R395 in the structure and stability of the quaternary NCF2/NCF4/VAV1/RAC1 NADPH oxidase complex. R395 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.
  • Posted in Journal of Biological Chemistry, Publications
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