How PTEN mutations degrade function at the membrane and life expectancy of carriers of mutations in the human brain.
How PTEN mutations degrade function at the membrane and life expectancy of carriers of mutations in the human brain.
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PTEN 突变如何降低人脑膜功能和突变携带者的预期寿命。
DOI：
10.1101/2023.01.26.525746
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Nussinov,Ruth
中科院分区：
文献类型：
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作者：
Jang,Hyunbum;Chen,Jiaye;Iakoucheva,LiliaM;Nussinov,Ruth
PTEN功能障碍是由脂质磷酸酶活性丧失或缺失引起的，可促进病理、癌症、良性肿瘤和神经发育障碍(NDDS)。尽管做出了努力，但这些突变到底是如何引发不同的表型结果，即癌症或NDD，一直令人费解。目前也不清楚如何区分异构体蕴含的突变，它们是癌症还是与NDDS相关的突变。在这里，我们将同时解决这两个问题。我们证明，PTEN突变以不同的变构方式影响P-环的动力学及其与催化部位的联系，从而影响催化活性。NDD相关突变可能会对野生型中存在的构象进行采样，而庇护癌症相关热点的采样构象倾向于催化构象，这表明NDD突变较弱。对异构体表达数据的分析表明，如果转录本有NDD相关突变，单独或与癌症热点结合，则存在高产前表达。如果在测量的天数内没有突变，则低表达水平。癌症突变促进更强的信号和细胞增殖；NDDS更弱，影响脑细胞分化。此外，外显子5受NDD或非NDD突变的影响，而外显子7仅受NDD突变的影响。我们全面的构象和基因组分析有助于发现相同的等位基因突变如何导致不同的临床表现，并揭示剪接异构体表达与预期寿命的相关性。
PTEN dysfunction, caused by loss of lipid phosphatase activity or deletion, promotes pathologies, cancer, benign tumors, and neurodevelopmental disorders (NDDs). Despite efforts, exactly how the mutations trigger distinct phenotypic outcomes, cancer or NDD, has been puzzling. It has also been unclear how to distinguish between mutations harbored by isoforms, are they cancer or NDDs-related. Here we address both. We demonstrate that PTEN mutations differentially allosterically bias P-loop dynamics and its connection to the catalytic site, affecting catalytic activity. NDD-related mutations are likely to sample conformations present in the wild-type, while sampled conformations sheltering cancer-related hotspots favor catalysis-prone conformations, suggesting that NDD mutations are weaker. Analysis of isoform expression data indicates that if the transcript has NDD-related mutations, alone or in combination with cancer hotspots, there is high prenatal expression. If no mutations within the measured days, low expression levels. Cancer mutations promote stronger signaling and cell proliferation; NDDs’ are weaker, influencing brain cell differentiation. Further, exon 5 is impacted by NDD or non-NDD mutations, while exon 7 is exclusively impacted by NDD mutations. Our comprehensive conformational and genomic analysis helps discover how same allele mutations can foster different clinical manifestations and uncovers correlations of splicing isoform expression to life expectancy.