The structural basis of PTEN regulation by multi-site phosphorylation

Daniel R. Dempsey; Thibault Viennet; Reina Iwase; Eunyoung Park; Stephanie Henriquez; Zan Chen; Jeliazko R. Jeliazkov; Brad A. Palanski; Kim L. Phan; Paul Coote; Jeffrey J. Gray; Michael J. Eck; Sandra B. Gabelli; Haribabu Arthanari; Philip A. Cole

doi:10.1038/s41594-021-00668-5

The structural basis of PTEN regulation by multi-site phosphorylation

Daniel R. Dempsey, Thibault Viennet, Reina Iwase, Eunyoung Park, Stephanie Henriquez, Zan Chen, Jeliazko R. Jeliazkov, Brad A. Palanski, Kim L. Phan, Paul Coote, Jeffrey J. Gray, Michael J. Eck, Sandra B. Gabelli^*, Haribabu Arthanari^*, Philip A. Cole^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

22 Citations (Scopus)

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.

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	https://doi.org/10.1038/s41594-021-00668-5
Publication status	Published - Oct 2021
Externally published	Yes

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Dempsey, D. R., Viennet, T., Iwase, R., Park, E., 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. (2021). The structural basis of PTEN regulation by multi-site phosphorylation. Nature Structural and Molecular Biology, 28(10), 858-868. https://doi.org/10.1038/s41594-021-00668-5

@article{55e4719c396642948ece9a61ceae8119,

title = "The structural basis of PTEN regulation by multi-site phosphorylation",

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{\textquoteright}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{\textquoteright}s cellular functions.",

author = "Dempsey, {Daniel R.} and Thibault Viennet and Reina Iwase and Eunyoung Park and Stephanie Henriquez and Zan Chen and Jeliazkov, {Jeliazko R.} and Palanski, {Brad A.} and Phan, {Kim L.} and Paul Coote and Gray, {Jeffrey J.} and Eck, {Michael J.} and Gabelli, {Sandra B.} and Haribabu Arthanari and Cole, {Philip A.}",

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year = "2021",

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doi = "10.1038/s41594-021-00668-5",

language = "English",

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T1 - The structural basis of PTEN regulation by multi-site phosphorylation

AU - Dempsey, Daniel R.

AU - Viennet, Thibault

AU - Iwase, Reina

AU - Park, Eunyoung

AU - Henriquez, Stephanie

AU - Chen, Zan

AU - Jeliazkov, Jeliazko R.

AU - Palanski, Brad A.

AU - Phan, Kim L.

AU - Coote, Paul

AU - Gray, Jeffrey J.

AU - Eck, Michael J.

AU - Gabelli, Sandra B.

AU - Arthanari, Haribabu

AU - Cole, Philip A.

PY - 2021/10

Y1 - 2021/10

N2 - 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.

AB - 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.

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DO - 10.1038/s41594-021-00668-5

M3 - Journal article

C2 - 34625746

AN - SCOPUS:85116791637

SN - 1545-9993

VL - 28

SP - 858

EP - 868

JO - Nature Structural and Molecular Biology

JF - Nature Structural and Molecular Biology

IS - 10

ER -

The structural basis of PTEN regulation by multi-site phosphorylation

Abstract

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