(156)PRO-]GLN SUBSTITUTION IN THE LIGHT-CHAIN OF CYTOCHROME B(558) OF THE HUMAN NADPH OXIDASE (P22-PHOX) LEADS TO DEFECTIVE TRANSLOCATION OF THE CYTOSOLIC PROTEINS P47-PHOX AND P67-PHOX

被引:91
作者
LEUSEN, JHW
BOLSCHER, BGJM
HILARIUS, PM
WEENING, RS
KAULFERSCH, W
SEGER, RA
ROOS, D
VERHOEVEN, AJ
机构
[1] UNIV AMSTERDAM,NETHERLANDS RED CROSS,BLOOD TRANSFUS SERV,CENT LAB,1066 CX AMSTERDAM,NETHERLANDS
[2] UNIV AMSTERDAM,EXPTL & CLIN IMMUNOL LAB,1066 CX AMSTERDAM,NETHERLANDS
[3] UNIV AMSTERDAM,ACAD MED CTR,EMMA CHILDRENS HOSP,DEPT PEDIAT,1105 AZ AMSTERDAM,NETHERLANDS
[4] HOSP KLAGENFURT,DEPT PEDIAT,A-9026 KLAGENFURT,AUSTRIA
[5] UNIV ZURICH,CHILDRENS HOSP,DEPT PEDIAT,DIV IMMUNOL HAEMATOL,CH-8032 ZURICH,SWITZERLAND
关键词
D O I
10.1084/jem.180.6.2329
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Src homology 3 (SH3) domains have been suggested to play an important role in the assembly of the superoxide-forming nicotinamide adenine dinucleotide phosphate (NADPH) oxidase upon activation of phagocytes, which involves the association of membrane-bound and cytosolic components. We studied the translocation of the cytosolic proteins to the plasma membrane in neutrophils of a patient with a point mutation in the gene encoding the light chain of cytochrome b(558). This mutation leads to a substitution at residue 156 of a proline into a glutamine in a putative SH3 binding domain of p22-phox (Dinauer, M., E. A. Pierce, R. W. Erickson, T. Muhlebach, H. Messner, R. A. Seger, S. H. Orkin, and J. T. Curnutte. 1991. Proc, Natl. Acad. Sci. 88:11231). In PMA-stimulated neutrophils and in a cell-free translocation assay with neutrophil membranes and cytosol, association of the cytosolic proteins p47-phox and p67-phox with the membrane fraction of the patient's neutrophils was virtually absent. In contrast, when solubilized membranes of the patient's neutrophils were activated with phospholipids in the absence of cytosol (Koshkin, V., and E. Pick. 1993. FEBS[Fed. Eur. Biochem. Soc]Lett. 327:57), the rate of NADPH-dependent oxygen uptake was observed at a rate similar to that of control membranes. We suggest that the binding of an SH3 domain of p47-phox to p22-phox, and thus activation of the oxidase, does not occur in the neutrophils of this patient, although under artificial conditions, electron flow from NADPH to oxygen in cytochrome b(558) is possible.
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收藏
页码:2329 / 2334
页数:6
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