Structure‐based Computational Modeling of Germline PTEN Mutations in Cancer and Autism Risk: Implications for Therapeutic Targeting

Abstract

The Phosphatase and TENsin homolog deleted on chromosome ten (PTEN) is a dual‐specificity phosphatase encoded by a tumor suppressor gene frequently somatically mutated in human cancer. Individuals with germline PTEN mutations are diagnosed with PTEN hamartoma tumor syndrome (PHTS). Clinically, PHTS has a variable phenotype spectrum, including distinct subsets of patients with autism spectrum disorder (ASD) and/or cancer. It remains unclear why mutations in one gene can lead to seemingly disparate phenotypes. Our pilot studies identified structural stability and functional differences in germline PTEN variants that contribute to cancer or to autismsuggesting distinct conformational disease states and a potential basis for allosteric communication via the inter‐domain region of PTEN. Thus, we hypothesized that key inter‐domain sites will delineate novel structurally correlated areas for potential drug targeting. Moreover, PTEN is inactivated by phosphorylation of C‐tail cluster sites (Ser/Thr residues 380‐385) which is known to play a critical role in the function and stability of PTEN. However, very little is known about the mechanism underlying such inactivation. We therefore sought to further understand whether C‐tail phosphorylation sites represent a possible phosphodegron motif that influences distinct conformational ensembles and inter‐domain interface specific to PTEN‐ASD and PTEN‐cancer phenotypes. By integrating in silico modeling, molecular simulations, and allosteric communication analyses we reveal the role of C‐tail phosphorylation on conformational dynamics and allosteric regulation of PTEN‐ASD and PTEN‐cancer phenotypes that exhibited the most exaggerated disease‐specific effects in our pilot studies. We show that C‐tail phosphorylation in PTEN‐ASD induces fluctuations in degradation‐sensitive sites (K13 and K289) that render a closed conformation. Furthermore, allosteric analysis reveals inter‐domain effector residues that strengthen the structural communication pathway. In contrast, a higher intrinsic flexibility and less stable conformational state emerges in PTEN‐cancer. Importantly, this reveals a less dense inter‐domain structural communication pathway that lacks effector degradation‐sensitive residues. Our integrative approach offers new insight into structurally correlated areas for potential drug targeting and will serve as the basis for designing novel therapeutics to attenuate PHTS‐associated cancer and ASD phenotypes.