biostudies-literatureSmith INAmbrose Monell FoundationNational Cancer InstituteNCI NIH HHSNational Institutes of HealthOhio Supercomputing CenterNational Institute of General Medical SciencesNIGMS NIH HHS4175-4190https://www.ebi.ac.uk/biostudies/studies/S-EPMC9472802biostudies-literatureUnknown62(17)The phosphatase and tensin homologue deleted on chromosome 10 (<i>PTEN</i>) tumor suppressor gene encodes a tightly regulated dual-specificity phosphatase that serves as the master regulator of PI3K/AKT/mTOR signaling. The carboxy-terminal tail (CTT) is key to regulation and harbors multiple phosphorylation sites (Ser/Thr residues 380-385). CTT phosphorylation suppresses the phosphatase activity by inducing a stable, closed conformation. However, little is known about the mechanisms of phosphorylation-induced CTT-deactivation dynamics. Using explicit solvent microsecond molecular dynamics simulations, we show that CTT phosphorylation leads to a partially collapsed conformation, which alters the secondary structure of PTEN and induces long-range conformational rearrangements that encompass the active site. The active site rearrangements prevent localization of PTEN to the membrane, precluding lipid phosphatase activity. Notably, we have identified phosphorylation-induced allosteric coupling between the interdomain region and a hydrophobic site neighboring the active site in the phosphatase domain. Collectively, the results provide a mechanistic understanding of CTT phosphorylation dynamics and reveal potential druggable allosteric sites in a previously believed clinically undruggable protein.Journal of chemical information and modelingStructural and Dynamic Effects of PTEN C-Terminal Tail Phosphorylation.PMC9472802PCCF0020R01 GM1392971K99GM143552-01K99 GM143552T32 CA059366P41 GM103712T32 5T32CA59366-22P41GM103712Dawson JESmith INThacker SBahar IKrieger JEng CfalseStructural and Dynamic Effects of PTEN C-Terminal Tail Phosphorylation.The phosphatase and tensin homologue deleted on chromosome 10 (<i>PTEN</i>) tumor suppressor gene encodes a tightly regulated dual-specificity phosphatase that serves as the master regulator of PI3K/AKT/mTOR signaling. The carboxy-terminal tail (CTT) is key to regulation and harbors multiple phosphorylation sites (Ser/Thr residues 380-385). CTT phosphorylation suppresses the phosphatase activity by inducing a stable, closed conformation. However, little is known about the mechanisms of phosphorylation-induced CTT-deactivation dynamics. Using explicit solvent microsecond molecular dynamics simulations, we show that CTT phosphorylation leads to a partially collapsed conformation, which alters the secondary structure of PTEN and induces long-range conformational rearrangements that encompass the active site. The active site rearrangements prevent localization of PTEN to the membrane, precluding lipid phosphatase activity. Notably, we have identified phosphorylation-induced allosteric coupling between the interdomain region and a hydrophobic site neighboring the active site in the phosphatase domain. Collectively, the results provide a mechanistic understanding of CTT phosphorylation dynamics and reveal potential druggable allosteric sites in a previously believed clinically undruggable protein.2022-01-01T00:00:00Z2022 Sep2026-05-28T01:56:40.075Z2025-04-04T20:28:51.946ZS-EPMC94728023600148110.1021/acs.jcim.2c00441