ALKBH7 Variant Related to Prostate Cancer Exhibits Altered Substrate Binding.
ALKBH7 Variant Related to Prostate Cancer Exhibits Altered Substrate Binding.
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DOI：
10.1371/journal.pcbi.1005345
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发表时间：
2017-02
影响因子：
4.3
通讯作者：
Cisneros GA
中科院分区：
文献类型：
--
作者：
Walker AR;Silvestrov P;Müller TA;Podolsky RH;Dyson G;Hausinger RP;Cisneros GA
前列腺癌生物标志物的研究受到了越来越多的关注，几种与DNA修复相关的酶被认为与这种功能障碍有关。在这里，我们报告了一项与前列腺癌相关的人ALKBH家族双加氧酶的单核苷酸多态(SNPs)和功能影响特征的有针对性的研究。我们的结果发现了ALKBH7的SNP，rs7540，在两个独立的队列中以统计上显著的方式与前列腺癌疾病相关，并在非裔美国人男性中保持。对野生型和变异型蛋白质结构的分子动力学(MD)模拟比较表明，由此导致的酶的改变导致了显著的结构变化，降低了ALKBH7的S结合其共底物的能力。对纯化蛋白的实验光谱学研究验证了我们的MD预测，并证实了这种与癌症相关的突变影响ALKBH7中的生产性共底物结合的结论。个性化DNA测序的改进导致了人们对用于治疗和诊断目的的靶向生物标记物的兴趣增加。在这项工作中，我们报告了一种新的前列腺癌生物标记物，它是通过有针对性地搜索人类ALKBH家族双加氧酶基因的单核苷酸多态(SNPs)而发现的。我们的结果发现了rs7540，这导致了ALKBH7的错义突变。对该蛋白野生型和单核苷酸多态性的比较分子动力学模拟表明，突变引起了结构的变化，显著降低了ALKBH7‘S对其共底物的亲和力。这一预测得到了实验UV-Vis光谱的证实。综上所述，这些结果为研究一种新的前列腺癌相关SNP及其对ALKBH7结构和功能的影响提供了重要的见解。
The search for prostate cancer biomarkers has received increased attention and several DNA repair related enzymes have been linked to this dysfunction. Here we report a targeted search for single nucleotide polymorphisms (SNPs) and functional impact characterization of human ALKBH family dioxygenases related to prostate cancer. Our results uncovered a SNP of ALKBH7, rs7540, which is associated with prostate cancer disease in a statistically significantly manner in two separate cohorts, and maintained in African American men. Comparisons of molecular dynamics (MD) simulations on the wild-type and variant protein structures indicate that the resulting alteration in the enzyme induces a significant structural change that reduces ALKBH7’s ability to bind its cosubstrate. Experimental spectroscopy studies with purified proteins validate our MD predictions and corroborate the conclusion that this cancer-associated mutation affects productive cosubstrate binding in ALKBH7. Improvements in personalized DNA sequencing have led to an increased interest in targeted biomarkers for therapeutic and diagnostic purposes. In this work, we report on a new biomarker for prostate cancer found through a targeted search for single nucleotide polymorphisms (SNPs) of the genes encoding human ALKBH family dioxygenases. Our results uncovered rs7540, which leads to a missense mutation in ALKBH7. Comparative molecular dynamics simulations on the wild type and SNP variant of the protein show that the mutation elicits a structural change that dramatically decreases ALKBH7’s affinity for its cosubstrate. This prediction is confirmed by experimental UV-Vis spectroscopy. Taken together, these results give important insights into a novel prostate-cancer related SNP and its impact on the structure and function of ALKBH7.