Cargando…

The mechanism of full activation of tumor suppressor PTEN at the phosphoinositide-enriched membrane

Tumor suppressor PTEN, the second most highly mutated protein in cancer, dephosphorylates signaling lipid PIP(3) produced by PI3Ks. Excess PIP(3) promotes cell proliferation. The mechanism at the membrane of this pivotal phosphatase is unknown hindering drug discovery. Exploiting explicit solvent si...

Descripción completa

Detalles Bibliográficos
Autores principales: Jang, Hyunbum, Smith, Iris Nira, Eng, Charis, Nussinov, Ruth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169795/
https://www.ncbi.nlm.nih.gov/pubmed/34113810
http://dx.doi.org/10.1016/j.isci.2021.102438
_version_ 1783702102121381888
author Jang, Hyunbum
Smith, Iris Nira
Eng, Charis
Nussinov, Ruth
author_facet Jang, Hyunbum
Smith, Iris Nira
Eng, Charis
Nussinov, Ruth
author_sort Jang, Hyunbum
collection PubMed
description Tumor suppressor PTEN, the second most highly mutated protein in cancer, dephosphorylates signaling lipid PIP(3) produced by PI3Ks. Excess PIP(3) promotes cell proliferation. The mechanism at the membrane of this pivotal phosphatase is unknown hindering drug discovery. Exploiting explicit solvent simulations, we tracked full-length PTEN trafficking from the cytosol to the membrane. We observed its interaction with membranes composed of zwitterionic phosphatidylcholine, anionic phosphatidylserine, and phosphoinositides, including signaling lipids PIP(2) and PIP(3). We tracked its moving away from the zwitterionic and getting absorbed onto anionic membrane that harbors PIP(3). We followed it localizing on microdomains enriched in signaling lipids, as PI3K does, and observed PIP(3) allosterically unfolding the N-terminal PIP(2) binding domain, positioning it favorably for the polybasic motif interaction with PIP(2). Finally, we determined PTEN catalytic action at the membrane, all in line with experimental observations, deciphering the mechanisms of how PTEN anchors to the membrane and restrains cancer.
format Online
Article
Text
id pubmed-8169795
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-81697952021-06-09 The mechanism of full activation of tumor suppressor PTEN at the phosphoinositide-enriched membrane Jang, Hyunbum Smith, Iris Nira Eng, Charis Nussinov, Ruth iScience Article Tumor suppressor PTEN, the second most highly mutated protein in cancer, dephosphorylates signaling lipid PIP(3) produced by PI3Ks. Excess PIP(3) promotes cell proliferation. The mechanism at the membrane of this pivotal phosphatase is unknown hindering drug discovery. Exploiting explicit solvent simulations, we tracked full-length PTEN trafficking from the cytosol to the membrane. We observed its interaction with membranes composed of zwitterionic phosphatidylcholine, anionic phosphatidylserine, and phosphoinositides, including signaling lipids PIP(2) and PIP(3). We tracked its moving away from the zwitterionic and getting absorbed onto anionic membrane that harbors PIP(3). We followed it localizing on microdomains enriched in signaling lipids, as PI3K does, and observed PIP(3) allosterically unfolding the N-terminal PIP(2) binding domain, positioning it favorably for the polybasic motif interaction with PIP(2). Finally, we determined PTEN catalytic action at the membrane, all in line with experimental observations, deciphering the mechanisms of how PTEN anchors to the membrane and restrains cancer. Elsevier 2021-04-17 /pmc/articles/PMC8169795/ /pubmed/34113810 http://dx.doi.org/10.1016/j.isci.2021.102438 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Jang, Hyunbum
Smith, Iris Nira
Eng, Charis
Nussinov, Ruth
The mechanism of full activation of tumor suppressor PTEN at the phosphoinositide-enriched membrane
title The mechanism of full activation of tumor suppressor PTEN at the phosphoinositide-enriched membrane
title_full The mechanism of full activation of tumor suppressor PTEN at the phosphoinositide-enriched membrane
title_fullStr The mechanism of full activation of tumor suppressor PTEN at the phosphoinositide-enriched membrane
title_full_unstemmed The mechanism of full activation of tumor suppressor PTEN at the phosphoinositide-enriched membrane
title_short The mechanism of full activation of tumor suppressor PTEN at the phosphoinositide-enriched membrane
title_sort mechanism of full activation of tumor suppressor pten at the phosphoinositide-enriched membrane
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169795/
https://www.ncbi.nlm.nih.gov/pubmed/34113810
http://dx.doi.org/10.1016/j.isci.2021.102438
work_keys_str_mv AT janghyunbum themechanismoffullactivationoftumorsuppressorptenatthephosphoinositideenrichedmembrane
AT smithirisnira themechanismoffullactivationoftumorsuppressorptenatthephosphoinositideenrichedmembrane
AT engcharis themechanismoffullactivationoftumorsuppressorptenatthephosphoinositideenrichedmembrane
AT nussinovruth themechanismoffullactivationoftumorsuppressorptenatthephosphoinositideenrichedmembrane
AT janghyunbum mechanismoffullactivationoftumorsuppressorptenatthephosphoinositideenrichedmembrane
AT smithirisnira mechanismoffullactivationoftumorsuppressorptenatthephosphoinositideenrichedmembrane
AT engcharis mechanismoffullactivationoftumorsuppressorptenatthephosphoinositideenrichedmembrane
AT nussinovruth mechanismoffullactivationoftumorsuppressorptenatthephosphoinositideenrichedmembrane