Jang Hyunbum, Chen Jiaye, Iakoucheva Lilia M, Nussinov Ruth
Computational Structural Biology Section, Frederick National Laboratory for Cancer Research in the Cancer Innovation Laboratory, National Cancer Institute, Frederick, MD 21702, U.S.A.
Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, U.S.A.
bioRxiv. 2023 Jan 27:2023.01.26.525746. doi: 10.1101/2023.01.26.525746.
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.
由脂质磷酸酶活性丧失或缺失引起的PTEN功能障碍会促进多种病症的发生，包括癌症、良性肿瘤和神经发育障碍（NDDs）。尽管人们付出了诸多努力，但这些突变究竟是如何引发不同的表型结果，即癌症或NDDs，一直是个谜。同样不清楚的是，如何区分异构体中携带的突变，它们是与癌症相关还是与NDDs相关。在这里，我们对这两个问题进行了探讨。我们证明，PTEN突变以不同方式通过变构作用影响P环动力学及其与催化位点的连接，进而影响催化活性。与NDD相关的突变可能会呈现野生型中存在的构象，而包含癌症相关热点的采样构象则有利于易于催化的构象，这表明与NDD相关的突变作用较弱。对异构体表达数据的分析表明，如果转录本具有与NDD相关的突变，单独或与癌症热点组合存在时，产前表达水平较高。如果在测量的时间段内没有突变，则表达水平较低。癌症相关突变会促进更强的信号传导和细胞增殖；而与NDDs相关的突变作用较弱，影响脑细胞分化。此外，外显子5会受到与NDD或非NDD相关突变的影响，而外显子7仅受与NDD相关突变的影响。我们全面的构象和基因组分析有助于发现相同等位基因突变如何引发不同的临床表现，并揭示剪接异构体表达与预期寿命之间的相关性。
