Name
Abstract | ||
|---|---|---|
The phosphatase and tensin homologue deleted on chromosome 10 () 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. |
Year | DOI | Venue |
|---|---|---|
2022 | 10.1021/acs.jcim.2c00441 | Journal of Chemical Information and Modeling |
DocType | Volume | Issue |
Journal | 62 | 17 |
ISSN | Citations | PageRank |
1549-9596 | 0 | 0.34 |
References | Authors | |
0 | 6 | |
Name | Order | Citations | PageRank |
|---|---|---|---|
| Iris N Smith | 1 | 0 | 0.34 |
| Jennifer E Dawson | 2 | 0 | 0.34 |
| James Krieger | 3 | 0 | 0.34 |
| Stetson Thacker | 4 | 0 | 0.34 |
| Ivet Bahar | 5 | 361 | 39.41 |
| Charis Eng | 6 | 10 | 2.28 |