Autopromotion of K-Ras4B Feedback Activation Through an SOS-Mediated Long-Range Allosteric Effect
The Ras-specific guanine nucleotide exchange factors Son of Sevenless (SOS) regulates Ras activation by converting inactive GDP-bound to active GTP-bound states. The catalytic activity of Ras is further allosterically regulated by GTP−Ras bound to a distal site through a positive feedback loop. To a...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9023742/ https://www.ncbi.nlm.nih.gov/pubmed/35463958 http://dx.doi.org/10.3389/fmolb.2022.860962 |
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author | He, Xuan Du, Kui Wang, Yuanhao Fan, Jigang Li, Mingyu Ni, Duan Lu, Shaoyong Bian, Xiaolan Liu, Yaqin |
author_facet | He, Xuan Du, Kui Wang, Yuanhao Fan, Jigang Li, Mingyu Ni, Duan Lu, Shaoyong Bian, Xiaolan Liu, Yaqin |
author_sort | He, Xuan |
collection | PubMed |
description | The Ras-specific guanine nucleotide exchange factors Son of Sevenless (SOS) regulates Ras activation by converting inactive GDP-bound to active GTP-bound states. The catalytic activity of Ras is further allosterically regulated by GTP−Ras bound to a distal site through a positive feedback loop. To address the mechanism underlying the long-range allosteric activation of the catalytic K-Ras4B by an additional allosteric GTP–Ras through SOS, we employed molecular dynamics simulation of the K-Ras4B(G13D)•SOS(cat) complex with and without an allosteric GTP-bound K-Ras4B(G13D). We found that the binding of an allosteric GTP−K-Ras4B(G13D) enhanced the affinity between the catalytic K-Ras4B(G13D) and SOS(cat), forming a more stable conformational state. The peeling away of the switch I from the nucleotide binding site facilitated the dissociation of GDP, thereby contributing to the increased nucleotide exchange rate. The community networks further showed stronger edge connection upon allosteric GTP−K-Ras4B(G13D) binding, which represented an increased interaction between catalytic K-Ras4B(G13D) and SOS(cat). Moreover, GTP−K-Ras4B(G13D) binding transmitted allosteric signaling pathways though the Cdc25 domain of SOS that enhanced the allosteric regulatory from the K-Ras4B(G13D) allosteric site to the catalytic site. This study may provide an in-depth mechanism for abnormal activation and allosteric regulation of K-Ras4B(G13D). |
format | Online Article Text |
id | pubmed-9023742 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-90237422022-04-23 Autopromotion of K-Ras4B Feedback Activation Through an SOS-Mediated Long-Range Allosteric Effect He, Xuan Du, Kui Wang, Yuanhao Fan, Jigang Li, Mingyu Ni, Duan Lu, Shaoyong Bian, Xiaolan Liu, Yaqin Front Mol Biosci Molecular Biosciences The Ras-specific guanine nucleotide exchange factors Son of Sevenless (SOS) regulates Ras activation by converting inactive GDP-bound to active GTP-bound states. The catalytic activity of Ras is further allosterically regulated by GTP−Ras bound to a distal site through a positive feedback loop. To address the mechanism underlying the long-range allosteric activation of the catalytic K-Ras4B by an additional allosteric GTP–Ras through SOS, we employed molecular dynamics simulation of the K-Ras4B(G13D)•SOS(cat) complex with and without an allosteric GTP-bound K-Ras4B(G13D). We found that the binding of an allosteric GTP−K-Ras4B(G13D) enhanced the affinity between the catalytic K-Ras4B(G13D) and SOS(cat), forming a more stable conformational state. The peeling away of the switch I from the nucleotide binding site facilitated the dissociation of GDP, thereby contributing to the increased nucleotide exchange rate. The community networks further showed stronger edge connection upon allosteric GTP−K-Ras4B(G13D) binding, which represented an increased interaction between catalytic K-Ras4B(G13D) and SOS(cat). Moreover, GTP−K-Ras4B(G13D) binding transmitted allosteric signaling pathways though the Cdc25 domain of SOS that enhanced the allosteric regulatory from the K-Ras4B(G13D) allosteric site to the catalytic site. This study may provide an in-depth mechanism for abnormal activation and allosteric regulation of K-Ras4B(G13D). Frontiers Media S.A. 2022-04-08 /pmc/articles/PMC9023742/ /pubmed/35463958 http://dx.doi.org/10.3389/fmolb.2022.860962 Text en Copyright © 2022 He, Du, Wang, Fan, Li, Ni, Lu, Bian and Liu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Molecular Biosciences He, Xuan Du, Kui Wang, Yuanhao Fan, Jigang Li, Mingyu Ni, Duan Lu, Shaoyong Bian, Xiaolan Liu, Yaqin Autopromotion of K-Ras4B Feedback Activation Through an SOS-Mediated Long-Range Allosteric Effect |
title | Autopromotion of K-Ras4B Feedback Activation Through an SOS-Mediated Long-Range Allosteric Effect |
title_full | Autopromotion of K-Ras4B Feedback Activation Through an SOS-Mediated Long-Range Allosteric Effect |
title_fullStr | Autopromotion of K-Ras4B Feedback Activation Through an SOS-Mediated Long-Range Allosteric Effect |
title_full_unstemmed | Autopromotion of K-Ras4B Feedback Activation Through an SOS-Mediated Long-Range Allosteric Effect |
title_short | Autopromotion of K-Ras4B Feedback Activation Through an SOS-Mediated Long-Range Allosteric Effect |
title_sort | autopromotion of k-ras4b feedback activation through an sos-mediated long-range allosteric effect |
topic | Molecular Biosciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9023742/ https://www.ncbi.nlm.nih.gov/pubmed/35463958 http://dx.doi.org/10.3389/fmolb.2022.860962 |
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