Shape shifting: The multiple conformational substates of the PTEN N-terminal PIP2-binding domain

The Phosphatase and TENsin homolog deleted on chromosome 10 (PTEN) is a chief regulator of a variety of cellular processes including cell proliferation, migration, growth, and death. It is also a major tumor suppressor gene that is frequently mutated or lost under cancerous conditions. PTEN encodes a dual-specificity (lipid and protein) phosphatase that negatively regulates the PI3K/AKT/mTOR signaling pathway where the PIP2-binding domain (PBD) regulates the lipid phosphatase function. Unfortunately, despite two decades of research, a full-length structure of PTEN remains elusive, leaving open questions regarding PTEN's disordered regions that mediate protein stability, post-translational modifications, protein-protein interactions, while also hindering the design of small molecules that can regulate PTEN's function. Here, we utilized a combination of crosslinking mass spectrometry, in silico predicted structural modeling (including AlphaFold2), molecular docking, molecular dynamics simulations, and residue interaction network modeling to obtain structural details and molecular insight into the behavior of the PBD of PTEN. Our study shows that the PBD exists in multiple conformations which suggests its ability to regulate PTEN's variety of functions. Studying how these specific conformational substates contribute to PTEN function is imperative to defining its function in disease pathogenesis, and to delineate ways to modulate its tumor suppressor activity.

Automated summary

PTEN, a chief regulator of cellular processes and a major tumor suppressor gene, remains elusive in terms of its structure and regulation of protein stability, post-translational modifications, and protein-protein interactions. In this study, multiple methods were employed to investigate the structure and molecular behavior of PTEN's PBD. The findings suggest that the PBD exists in multiple conformations, highlighting the importance of understanding how these specific conformational substates contribute to PTEN function, disease pathogenesis, and modulation of its tumor suppressor activity.