导致 PTEN 脂质磷酸酶活性丧失的突变可促进癌症、良性肿瘤 (PHTS) 和神经发育障碍 (NDD)。它们究竟如何优先触发不同的表型结果一直令人困惑。在这里，我们证明 PTEN 突变对 P 环动力学及其与催化位点的连接存在不同的变构偏差，从而影响催化活性。 NDD 相关突变可能会采样功能性野生型状态的构象，而强的、与癌症相关的驱动突变热点的采样构象则有利于催化引发的构象，这表明 NDD 突变可能较弱，而我们的大-规模模拟揭示了原因。产前 PTEN 亚型表达数据表明，携带 NDD 突变的外显子 5 和 7 是癌症风险携带者。由于癌症需要多个突变，我们的构象和基因组分析有助于发现相同的蛋白质突变如何促进不同的临床表现，阐明同时发生的背景潜在驱动突变的作用，并揭示剪接亚型表达与预期寿命的关系。版权© 2023。由爱思唯尔有限公司出版。

Mutations causing loss of PTEN lipid phosphatase activity can promote cancer, benign tumors (PHTS), and neurodevelopmental disorders (NDDs). Exactly how they preferentially trigger distinct phenotypic outcomes has been puzzling. Here, 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 of the functional wild-type state, while sampled conformations for the strong, cancer-related driver mutation hotspots favor catalysis-primed conformations, suggesting that NDD mutations are likely to be weaker, and our large-scale simulations show why. Prenatal PTEN isoform expression data suggest exons 5 and 7, which harbor NDD mutations, as cancer-risk carriers. Since cancer requires more than a single mutation, our conformational and genomic analysis helps discover how same protein mutations can foster different clinical manifestations, articulates a role for co-occurring background latent driver mutations, and uncovers relationships of splicing isoform expression to life expectancy.Copyright © 2023. Published by Elsevier Ltd.