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摘要 : 2016年12月7日,国际著名学术杂志《Cell》子刊《AJHG》杂志在线发表了上海交通大学医学院细胞分化与凋亡重点实验室张健课题组和美国范德堡大学赵中明教授研究组在变构领域的最新成果

 2016年12月7日,国际著名学术杂志《Cell》子刊《AJHG》杂志在线发表了上海交通大学医学院细胞分化与凋亡重点实验室张健课题组和美国范德堡大学赵中明教授研究组在变构领域的最新成果:Proteome-scale investigation of protein allosteric regulation perturbed by somatic mutations in 7,000 cancer genomes,研究论文报告其发展了通过大规模肿瘤基因组在蛋白结构上的变构映射精准识别各类型肿瘤全新靶标的方法,并利用该方法发现非小细胞肺癌的全新靶标PDE10A。张健课题组的沈倩诚博士以及美国哈佛医学院的程飞雄博士为论文的第一作者,赵中明教授和张健研究员为论文的共同通讯作者。




Proteome-Scale Investigation of Protein Allosteric Regulation Perturbed by Somatic Mutations in 7,000 Cancer Genomes


The allosteric regulation triggering the protein’s functional activity via conformational changes is an intrinsic function of protein under many physiological and pathological conditions, including cancer. Identification of the biological effects of specific somatic variants on allosteric proteins and the phenotypes that they alter during tumor initiation and progression is a central challenge for cancer genomes in the post-genomic era. Here, we mapped more than 47,000 somatic missense mutations observed in approximately 7,000 tumor-normal matched samples across 33 cancer types into protein allosteric sites to prioritize the mutated allosteric proteins and we tested our prediction in cancer cell lines. We found that the deleterious mutations identified in cancer genomes were more significantly enriched at protein allosteric sites than tolerated mutations, suggesting a critical role for protein allosteric variants in cancer. Next, we developed a statistical approach, namely AlloDriver, and further identified 15 potential mutated allosteric proteins during pan-cancer and individual cancer-type analyses. More importantly, we experimentally confirmed that p.Pro360Ala on PDE10A played a potential oncogenic role in mediating tumorigenesis in non-small cell lung cancer (NSCLC). In summary, these findings shed light on the role of allosteric regulation during tumorigenesis and provide a useful tool for the timely development of targeted cancer therapies.

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