2021
Dempsey, D. R.; Viennet, T.; Iwase, R.; Park, E. Y.; Henriquez, S.; Chen, Z.; Jeliazkov, J. R.; Palanski, B. A.; Phan, K. L.; Coote, P.; Gray, J. J.; Eck, M. J.; Gabelli, S. B.; Arthanari, H.; Cole, P. A.
The structural basis of PTEN regulation by multi-site phosphorylation Journal Article
In: Nat. Struct. Mol. Biol., vol. 28, no. 10, pp. 858-868, 2021, ISSN: 1545-9985.
Abstract | Links | BibTeX | Tags: Animals, Ciona intestinalis, Crystallography, Fluorescence Polarization, Humans, Magnetic Resonance Spectroscopy, Molecular Docking Simulation, Phosphorylation, PTEN Phosphohydrolase, X-Ray
@article{1624365,
title = {The structural basis of PTEN regulation by multi-site phosphorylation},
author = {D. R. Dempsey and T. Viennet and R. Iwase and E. Y. Park and S. Henriquez and Z. Chen and J. R. Jeliazkov and B. A. Palanski and K. L. Phan and P. Coote and J. J. Gray and M. J. Eck and S. B. Gabelli and H. Arthanari and P. A. Cole},
doi = {10.1038/s41594-021-00668-5},
issn = {1545-9985},
year = {2021},
date = {2021-10-28},
urldate = {2021-10-28},
journal = {Nat. Struct. Mol. Biol.},
volume = {28},
number = {10},
pages = {858-868},
abstract = {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.},
keywords = {Animals, Ciona intestinalis, Crystallography, Fluorescence Polarization, Humans, Magnetic Resonance Spectroscopy, Molecular Docking Simulation, Phosphorylation, PTEN Phosphohydrolase, X-Ray},
pubstate = {published},
tppubtype = {article}
}
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.