Elucidating PTEN Conformational Dynamics and Phosphatase Regulation via Integrative Modeling and Mutation Prediction

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 phospho-regulated 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.