Disturbed interaction of p21-rac with mutated p67-phox causes chronic granulomatous disease
Disturbed interaction of p21-rac with mutated p67-phox causes chronic granulomatous disease
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p21-rac 与突变 p67-phox 相互作用的紊乱导致慢性肉芽肿病
DOI：
--
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发表时间：
1996
影响因子：
15.3
通讯作者：
D. Roos
中科院分区：
文献类型：
--
作者：
Jeanette H. W. Leusen;Angelique De Klein;Petra M. Hilarius;Anders lhlinfi;Jan Palmblad;C I Edvard Smith;Dagmar Diekmann;Alan Hall;Arthur J. Verhoeven;D. Roos
慢性肉芽肿性疾病(CGD)的特征是吞噬的白细胞不能产生细胞内杀灭微生物所需的超氧化物。这是由烟酰胺腺嘌呤二核苷酸磷酸(NADPH)氧化酶四个亚基中的任何一个突变引起的。在一种罕见的常染色体隐性形式的CGD中，这种酶的一个67kD的胞浆成分(p67-Phox)缺失。我们在此报告一例p67-Phox基因突变导致无功能p67-Phox蛋白表达的患者。这位患者的纯化的粒细胞不能产生超氧化物，并且含有大约正常数量的p67-Phox。对该患者的cDNA和基因组DNA的分析表明，该患者是p67-Phox基因三重核苷酸缺失的复合杂合子，预示着p67-Phox蛋白中58个赖氨酸的框内缺失，以及另一个等位基因11-13kb的更大缺失。有趣的是，p67-Phox中58Lys的缺失破坏了与p21-rac1的相互作用，p21-rac1是一种参与NADPH氧化酶激活的ras相关蛋白。与正常的中性粒细胞不同，p47-Phox和p67-Phox在细胞激活时转移到质膜上，而患者的细胞没有表现出这种移位，这表明p67-Phox和p21-rac1之间的相互作用对于这些胞浆蛋白的移位和NADPH氧化酶的激活是必不可少的。此外，这位CGD患者是首例由ras相关蛋白与其目标蛋白结合紊乱引起的疾病。
Chronic granulomatous disease (CGD) is characterized by the failure of phagocytic leukocytes to generate superoxide, needed for the intracellular killing of microorganisms. This is caused by mutations in any one of the four subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In a rare, autosomal recessive form of CGD, a 67-kD cytosolic component of this enzyme (p67-phox) is missing. We here report on a patient with a mutation in the p67-phox gene that leads to expression of a nonfunctional p67-phox protein. The purified granulocytes of this patient failed to produce superoxide and contained about half of the normal amount of p67-phox. Analysis of the cDNA and genomic DNA of this patient showed that the patient is a compound heterozygote for a triplet nucleotide deletion in the p67-phox gene, predicting an in-frame deletion of lysine 58 in the p67-phox protein and a larger deletion of 11-13 kb in the other allele. Interestingly, the 58Lys deletion in p67-phox disrupts the interaction with p21-rac1, a ras-related protein involved in the activation of the NADPH oxidase. In contrast to normal neutrophils, in which p47-phox and p67-phox translocate to the plasma membrane upon cell activation, the cells of the patient did not show this translocation, indicating that an interaction between p67-phox and p21-rac1 is essential for translocation of these cytosolic proteins and activation of the NADPH oxidase. Moreover, this CGD patient represents the first case of disease caused by a disturbed binding of a ras-related protein to its target protein.
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影响因子：
15.9
作者：
DINAUER, MC;PIERCE, EA;ORKIN, SH
通讯作者：
ORKIN, SH
影响因子：
56.9
作者：
LETO, TL;LOMAX, KJ;MALECH, HL
通讯作者：
MALECH, HL
用佛波醇肉豆蔻酸酯乙酸酯刺激后，人中性粒细胞中 NADPH:O2 氧化还原酶的组装和激活。
DOI：
--
发表时间：
1990
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Ambruso,DR;Bolscher,BG;Stokman,PM;Verhoeven,AJ;Roos,D
通讯作者：
Roos,D
DOI：
10.1073/pnas.86.18.7195
发表时间：
1989-09
影响因子：
11.1
作者：
B. Volpp;W. Nauseef;J. Donelson;D. Moser;R. Clark
通讯作者：
B. Volpp;W. Nauseef;J. Donelson;D. Moser;R. Clark
影响因子：
15.9
作者：
CLARK, RA;VOLPP, BD;NAUSEEF, WM
通讯作者：
NAUSEEF, WM