Cargando…

Exploring the Distinct Binding and Activation Mechanisms for Different CagA Oncoproteins and SHP2 by Molecular Dynamics Simulations

CagA is a major virulence factor of Helicobacter pylori. H. pylori CagA is geographically subclassified into East Asian CagA and Western CagA, which are characterized by the presence of a EPIYA-D or EPIYA-C segment. The East Asian CagA is more closely associated with gastric cancer than the Western...

Descripción completa

Detalles Bibliográficos
Autores principales: Wang, Quan, Zhao, Wen-Cheng, Fu, Xue-Qi, Zheng, Qing-Chuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916045/
https://www.ncbi.nlm.nih.gov/pubmed/33562680
http://dx.doi.org/10.3390/molecules26040837
_version_ 1783657389170360320
author Wang, Quan
Zhao, Wen-Cheng
Fu, Xue-Qi
Zheng, Qing-Chuan
author_facet Wang, Quan
Zhao, Wen-Cheng
Fu, Xue-Qi
Zheng, Qing-Chuan
author_sort Wang, Quan
collection PubMed
description CagA is a major virulence factor of Helicobacter pylori. H. pylori CagA is geographically subclassified into East Asian CagA and Western CagA, which are characterized by the presence of a EPIYA-D or EPIYA-C segment. The East Asian CagA is more closely associated with gastric cancer than the Western CagA. In this study, molecular dynamic (MD) simulations were performed to investigate the binding details of SHP2 and EPIYA segments, and to explore the allosteric regulation mechanism of SHP2. Our results show that the EPIYA-D has a stronger binding affinity to the N-SH2 domain of SHP2 than EPIYA-C. In addition, a single EPIYA-D binding to N-SH2 domain of SHP2 can cause a deflection of the key helix B, and the deflected helix B could squeeze the N-SH2 and PTP domains to break the autoinhibition pocket of SHP2. However, a single EPIYA-C binding to the N-SH2 domain of SHP2 cannot break the autoinhibition of SHP2 because the secondary structure of the key helix B is destroyed. However, the tandem EPIYA-C not only increases its binding affinity to SHP2, but also does not significantly break the secondary structure of the key helix B. Our study can help us better understand the mechanism of gastric cancer caused by Helicobacter pylori infection.
format Online
Article
Text
id pubmed-7916045
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-79160452021-03-01 Exploring the Distinct Binding and Activation Mechanisms for Different CagA Oncoproteins and SHP2 by Molecular Dynamics Simulations Wang, Quan Zhao, Wen-Cheng Fu, Xue-Qi Zheng, Qing-Chuan Molecules Article CagA is a major virulence factor of Helicobacter pylori. H. pylori CagA is geographically subclassified into East Asian CagA and Western CagA, which are characterized by the presence of a EPIYA-D or EPIYA-C segment. The East Asian CagA is more closely associated with gastric cancer than the Western CagA. In this study, molecular dynamic (MD) simulations were performed to investigate the binding details of SHP2 and EPIYA segments, and to explore the allosteric regulation mechanism of SHP2. Our results show that the EPIYA-D has a stronger binding affinity to the N-SH2 domain of SHP2 than EPIYA-C. In addition, a single EPIYA-D binding to N-SH2 domain of SHP2 can cause a deflection of the key helix B, and the deflected helix B could squeeze the N-SH2 and PTP domains to break the autoinhibition pocket of SHP2. However, a single EPIYA-C binding to the N-SH2 domain of SHP2 cannot break the autoinhibition of SHP2 because the secondary structure of the key helix B is destroyed. However, the tandem EPIYA-C not only increases its binding affinity to SHP2, but also does not significantly break the secondary structure of the key helix B. Our study can help us better understand the mechanism of gastric cancer caused by Helicobacter pylori infection. MDPI 2021-02-05 /pmc/articles/PMC7916045/ /pubmed/33562680 http://dx.doi.org/10.3390/molecules26040837 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wang, Quan
Zhao, Wen-Cheng
Fu, Xue-Qi
Zheng, Qing-Chuan
Exploring the Distinct Binding and Activation Mechanisms for Different CagA Oncoproteins and SHP2 by Molecular Dynamics Simulations
title Exploring the Distinct Binding and Activation Mechanisms for Different CagA Oncoproteins and SHP2 by Molecular Dynamics Simulations
title_full Exploring the Distinct Binding and Activation Mechanisms for Different CagA Oncoproteins and SHP2 by Molecular Dynamics Simulations
title_fullStr Exploring the Distinct Binding and Activation Mechanisms for Different CagA Oncoproteins and SHP2 by Molecular Dynamics Simulations
title_full_unstemmed Exploring the Distinct Binding and Activation Mechanisms for Different CagA Oncoproteins and SHP2 by Molecular Dynamics Simulations
title_short Exploring the Distinct Binding and Activation Mechanisms for Different CagA Oncoproteins and SHP2 by Molecular Dynamics Simulations
title_sort exploring the distinct binding and activation mechanisms for different caga oncoproteins and shp2 by molecular dynamics simulations
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916045/
https://www.ncbi.nlm.nih.gov/pubmed/33562680
http://dx.doi.org/10.3390/molecules26040837
work_keys_str_mv AT wangquan exploringthedistinctbindingandactivationmechanismsfordifferentcagaoncoproteinsandshp2bymoleculardynamicssimulations
AT zhaowencheng exploringthedistinctbindingandactivationmechanismsfordifferentcagaoncoproteinsandshp2bymoleculardynamicssimulations
AT fuxueqi exploringthedistinctbindingandactivationmechanismsfordifferentcagaoncoproteinsandshp2bymoleculardynamicssimulations
AT zhengqingchuan exploringthedistinctbindingandactivationmechanismsfordifferentcagaoncoproteinsandshp2bymoleculardynamicssimulations