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The structural basis of PTEN regulation by multi-site phosphorylation
Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review
DOI
- https://doi.org/10.1038/s41594-021-00668-5
Final published version
- Daniel R. Dempsey, Harvard University, Brigham and Women's Hospital ,
- Thibault Viennet
- Reina Iwase, Harvard University, Brigham and Women's Hospital ,
- Eunyoung Park, Harvard University, Dana-Farber Cancer Institute ,
- Stephanie Henriquez, Johns Hopkins University ,
- Zan Chen, Johns Hopkins University ,
- Jeliazko R. Jeliazkov, Johns Hopkins University ,
- Brad A. Palanski, Harvard University, Brigham and Women's Hospital ,
- Kim L. Phan, Johns Hopkins University ,
- Paul Coote, Harvard University, Dana-Farber Cancer Institute ,
- Jeffrey J. Gray, Johns Hopkins University ,
- Michael J. Eck, Harvard University, Dana-Farber Cancer Institute ,
- Sandra B. Gabelli, Johns Hopkins University ,
- Haribabu Arthanari, Harvard University, Dana-Farber Cancer Institute ,
- Philip A. Cole, Harvard University, Brigham and Women's Hospital
Phosphatase and tensin homolog (PTEN) is a phosphatidylinositol-3,4,5-triphosphate (PIP3) phospholipid phosphatase that is commonly mutated or silenced in cancer. PTEN’s catalytic activity, cellular membrane localization and stability are orchestrated by a cluster of C-terminal phosphorylation (phospho-C-tail) events on Ser380, Thr382, Thr383 and Ser385, but the molecular details of this multi-faceted regulation have remained uncertain. Here we use a combination of protein semisynthesis, biochemical analysis, NMR, X-ray crystallography and computational simulations on human PTEN and its sea squirt homolog, VSP, to obtain a detailed picture of how the phospho-C-tail forms a belt around the C2 and phosphatase domains of PTEN. We also visualize a previously proposed dynamic N-terminal α-helix and show that it is key for PTEN catalysis but disordered upon phospho-C-tail interaction. This structural model provides a comprehensive framework for how C-tail phosphorylation can impact PTEN’s cellular functions.
| Original language | English |
|---|---|
| Journal | Nature Structural and Molecular Biology |
| Volume | 28 |
| Issue | 10 |
| Pages (from-to) | 858-868 |
| Number of pages | 11 |
| ISSN | 1545-9993 |
| DOIs | |
| Publication status | Published - Oct 2021 |
| Externally published | Yes |
Bibliographical note
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
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