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Updated: Sep 16, 2025
Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
Elucidating PTEN conformational dynamics and phosphatase regulation via integrative modeling and mutation prediction
Jennifer Erin Dawson1, Iris Nira Smith1, Ann Marie Tushar1
1Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, OH 44195, USA.
Abstract:
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.
Insights
PTEN protein's structure changes between open and closed forms, affecting its tumor suppressor function. Understanding these conformational shifts aids in predicting the impact of PTEN mutations in cancer.
Area of Science:
- Molecular Biology
- Structural Biology
- Cancer Research
Background:
- PTEN (Phosphatase and TENsin homolog deleted on chromosome ten) is a critical tumor suppressor gene frequently altered in cancer.
- PTEN negatively regulates the PI3K/AKT/mTOR pathway, a key pathway in cell growth and survival, at the plasma membrane.
- PTEN's function and localization are dictated by its conformational state, with open and closed forms regulating plasma membrane access.
Purpose of the Study:
- To elucidate the structural mechanisms underlying PTEN's conformational changes and their impact on function.
- To investigate the relationship between PTEN conformation, plasma membrane binding, and catalytic activity.
- To improve the prediction of PTEN mutation consequences using structural insights.
Main Methods:
- Integrative structural modeling approach.
- Coarse-grained and all-atom molecular dynamics simulations.
- Experimental crosslinking mass spectrometry.
Main Results:
- Identified conformational exchange between an 'eased' and a 'strained' PTEN form.
- The 'strained' form brings phosphatase and C2 domains together, obstructing the catalytic site and altering plasma membrane-binding loops.
- Developed full-length PTEN models, integrated with AlphaMissense and RaSP, for enhanced mutation consequence prediction.
Conclusions:
- PTEN's conformational dynamics are crucial for its tumor suppressor activity.
- The interplay between PTEN's domains and its localization is conformationally regulated.
- Structural modeling provides a framework for understanding PTEN mutations in cancer.
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