Dawson Jennifer Erin, Smith Iris Nira, Tushar Ann Marie, Eng Charis
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, OH 44195, USA.
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, OH 44195, USA.
Structure. 2025 Jun 30. doi: 10.1016/j.str.2025.06.002.
PTEN (Phosphatase and TENsin homolog deleted on chromosome ten) is a major tumor suppressor gene that is frequently mutated or lost under cancerous conditions. PTEN is a dual-specificity phosphatase that negatively regulates the PI3K/AKT/mTOR signaling pathway at the plasma membrane (PM). Its functional regulation and cellular localization are known to be conformationally driven. Access to the PM is phosphoregulated by open and closed PTEN forms. However, clarifying the underlying structural mechanisms is still an open avenue of research. Here, we apply an integrative structural modeling approach, combining coarse-grained and all-atom molecular dynamics with experimental crosslinking mass spectrometry. Conformational exchange between an "eased" form and a "strained" form brings the protein's phosphatase and C2 domains closer together, blocking the catalytic site, and affecting the loops involved in PM binding. Our full-length PTEN models, AlphaMissense, and RaSP were used to better predict the consequences of PTEN mutations.
PTEN（第10号染色体缺失的磷酸酶和张力蛋白同源物）是一种主要的肿瘤抑制基因，在癌症状态下经常发生突变或缺失。PTEN是一种双特异性磷酸酶，在质膜（PM）上对PI3K/AKT/mTOR信号通路进行负调控。已知其功能调节和细胞定位受构象驱动。PTEN通过开放和闭合形式对进入质膜进行磷酸化调节。然而，阐明其潜在的结构机制仍是一个有待探索的研究方向。在此，我们应用一种综合结构建模方法，将粗粒度和全原子分子动力学与实验交联质谱相结合。“松弛”形式和“紧张”形式之间的构象交换使蛋白质的磷酸酶和C2结构域靠得更近，阻断催化位点，并影响参与质膜结合的环。我们的全长PTEN模型、AlphaMissense和RaSP被用于更好地预测PTEN突变的后果。
