Structural analysis of clinically relevant pathogenic G6PD variants reveals the importance of tetramerization for G6PD activity.
Structural analysis of clinically relevant pathogenic G6PD variants reveals the importance of tetramerization for G6PD activity.
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DOI：
10.19185/matters.201705000008
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发表时间：
2017-09-14
期刊：
影响因子：
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通讯作者：
Mochly-Rosen D
中科院分区：
文献类型：
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作者：
Cunningham AD;Mochly-Rosen D
在人类葡萄糖-6-磷酸脱氢酶（G6PD）中，已经发现了220多种不同的氨基酸变体，覆盖了超过30%的蛋白质序列。这些变异中的许多是致病性的，导致不同程度的G6PD缺乏症，症状从严重的慢性贫血（I类）到轻度触发的溶血发作（II类和III类）。大多数G6PD变异的表型效应已被报道，提供了将表型和结构信息联系起来的机会。特别是，我们试图研究G6PD的四聚体界面与致病变异的关系，因为有相互矛盾的报道表明四聚体对G6PD活性的重要性。利用三维空间扫描统计，确定了每一类致病性G6PD变异的结构富集热点。表型最严重的I类变异在二聚体界面富集，这与先前的证据一致，即二聚体对G6PD活性至关重要。II类变体在四聚体界面附近富集，表明四聚化对G6PD活性也很重要。这一分析解释了为什么这两类患者的G6PD活性都比正常患者低10%或更低，却会导致不同的临床结果。
Over 220 different amino acid variants have been identified in human glucose-6-phosphate dehydrogenase (G6PD), covering over 30% of the protein sequence. Many of these variants are pathogenic, causing varying degrees of G6PD deficiency with symptoms ranging from severe chronic anemia (class I) to milder triggered hemolytic episodes (classes II and III). The phenotypic effects of most G6PD variants have been reported, providing an opportunity to correlate phenotypic and structural information. In particular, we sought to investigate the tetramer interface of G6PD in relation to pathogenic variation, as there are conflicting reports indicating the importance of tetramerization for G6PD activity. Using a three-dimensional spatial scan statistic, hotspots of structural enrichment were identified for each class of pathogenic G6PD variants. Class I variants, the most phenotypically severe, were enriched at the dimer interface, consistent with previous evidence that dimerization is essential for G6PD activity. Class II variants were enriched near the tetramer interface, suggesting that tetramerization is also important for G6PD activity. This analysis explains why these two classes, both yielding 10% or less G6PD activity as compared to normal, lead to different clinical outcomes.