{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Smith IN"],"funding":["Ambrose Monell Foundation","National Cancer Institute","NCI NIH HHS","National Institutes of Health","Ohio Supercomputing Center","National Institute of General Medical Sciences","NIGMS NIH HHS"],"pagination":["4175-4190"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9472802"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["62(17)"],"pubmed_abstract":["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":["Journal of chemical information and modeling"],"pubmed_title":["Structural and Dynamic Effects of PTEN C-Terminal Tail Phosphorylation."],"pmcid":["PMC9472802"],"funding_grant_id":["PCCF0020","R01 GM139297","1K99GM143552-01","K99 GM143552","T32 CA059366","P41 GM103712","T32 5T32CA59366-22","P41GM103712"],"pubmed_authors":["Dawson JE","Smith IN","Thacker S","Bahar I","Krieger J","Eng C"],"additional_accession":[]},"is_claimable":false,"name":"Structural and Dynamic Effects of PTEN C-Terminal Tail Phosphorylation.","description":"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.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Sep","modification":"2026-05-28T01:56:40.075Z","creation":"2025-04-04T20:28:51.946Z"},"accession":"S-EPMC9472802","cross_references":{"pubmed":["36001481"],"doi":["10.1021/acs.jcim.2c00441"]}}