A novel partially open state of SHP2 points to a “multiple gear” regulation mechanism

The protein tyrosine phosphatase SHP2 mediates multiple signal transductions in various cellular pathways, controlled by a variety of upstream inputs. SHP2 dysregulation is causative of different types of cancers and developmental disorders, making it a promising drug target. However, how SHP2 is mo...

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Published inThe Journal of biological chemistry Vol. 296; p. 100538
Main Authors Tao, Youqi, Xie, Jingfei, Zhong, Qinglu, Wang, Yongyao, Zhang, Shengnan, Luo, Feng, Wen, Fengcai, Xie, Jingjing, Zhao, Jiawei, Sun, Xiaoou, Long, Houfang, Ma, Junfeng, Zhang, Qian, Long, Jiangang, Fang, Xianyang, Lu, Ying, Li, Dan, Li, Ming, Zhu, Jidong, Sun, Bo, Li, Guohui, Diao, Jiajie, Liu, Cong
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 01.01.2021
American Society for Biochemistry and Molecular Biology
Subjects
allosteric regulation
conformational change
fluorescence resonance energy transfer
single-molecule biophysics
tyrosine-protein phosphatase (tyrosine phosphatase)
single-molecule biophysics
TDP
IRS-1
ABMD
fluorescence resonance energy transfer
tyrosine-protein phosphatase (tyrosine phosphatase)
allosteric regulation
smFRET
conformational change
TIRF
SAXS
DiFMUP
MD
TCEP
fluorescence resonance energy transfer (FRET)
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Abstract The protein tyrosine phosphatase SHP2 mediates multiple signal transductions in various cellular pathways, controlled by a variety of upstream inputs. SHP2 dysregulation is causative of different types of cancers and developmental disorders, making it a promising drug target. However, how SHP2 is modulated by its different regulators remains largely unknown. Here, we use single-molecule fluorescence resonance energy transfer and molecular dynamics simulations to investigate this question. We identify a partially open, semiactive conformation of SHP2 that is intermediate between the known open and closed states. We further demonstrate a “multiple gear” regulatory mechanism, in which different activators (e.g., insulin receptor substrate-1 and CagA), oncogenic mutations (e.g., E76A), and allosteric inhibitors (e.g., SHP099) can shift the equilibrium of the three conformational states and regulate SHP2 activity to different levels. Our work reveals the essential role of the intermediate state in fine-tuning the activity of SHP2, which may provide new opportunities for drug development for relevant cancers.
AbstractList The protein tyrosine phosphatase SHP2 mediates multiple signal transductions in various cellular pathways, controlled by a variety of upstream inputs. SHP2 dysregulation is causative of different types of cancers and developmental disorders, making it a promising drug target. However, how SHP2 is modulated by its different regulators remains largely unknown. Here, we use single-molecule fluorescence resonance energy transfer and molecular dynamics simulations to investigate this question. We identify a partially open, semiactive conformation of SHP2 that is intermediate between the known open and closed states. We further demonstrate a “multiple gear” regulatory mechanism, in which different activators ( e.g., insulin receptor substrate-1 and CagA), oncogenic mutations ( e.g., E76A), and allosteric inhibitors ( e.g., SHP099) can shift the equilibrium of the three conformational states and regulate SHP2 activity to different levels. Our work reveals the essential role of the intermediate state in fine-tuning the activity of SHP2, which may provide new opportunities for drug development for relevant cancers.
The protein tyrosine phosphatase SHP2 mediates multiple signal transductions in various cellular pathways, controlled by a variety of upstream inputs. SHP2 dysregulation is causative of different types of cancers and developmental disorders, making it a promising drug target. However, how SHP2 is modulated by its different regulators remains largely unknown. Here, we use single-molecule fluorescence resonance energy transfer (smFRET) and molecular dynamics (MD) simulations to investigate this question. We identify a partially-open, semi-active conformation of SHP2 that is intermediate between the known open and closed states. We further demonstrate a "multiple gear" regulatory mechanism, in which different activators (e.g. IRS-1 and CagA), oncogenic mutations (e.g. E76A) and allosteric inhibitors (e.g. SHP099) can shift the equilibrium of the three conformational states and regulate SHP2 activity to different levels. Our work reveals the essential role of the intermediate state in fine-tuning the activity of SHP2, which may provide new opportunities for drug development for relevant cancers.
The protein tyrosine phosphatase SHP2 mediates multiple signal transductions in various cellular pathways, controlled by a variety of upstream inputs. SHP2 dysregulation is causative of different types of cancers and developmental disorders, making it a promising drug target. However, how SHP2 is modulated by its different regulators remains largely unknown. Here, we use single-molecule fluorescence resonance energy transfer and molecular dynamics simulations to investigate this question. We identify a partially open, semiactive conformation of SHP2 that is intermediate between the known open and closed states. We further demonstrate a “multiple gear” regulatory mechanism, in which different activators (e.g., insulin receptor substrate-1 and CagA), oncogenic mutations (e.g., E76A), and allosteric inhibitors (e.g., SHP099) can shift the equilibrium of the three conformational states and regulate SHP2 activity to different levels. Our work reveals the essential role of the intermediate state in fine-tuning the activity of SHP2, which may provide new opportunities for drug development for relevant cancers.
ArticleNumber 100538
Author Wen, Fengcai
Li, Dan
Li, Ming
Zhu, Jidong
Zhong, Qinglu
Long, Houfang
Sun, Bo
Wang, Yongyao
Zhang, Qian
Ma, Junfeng
Li, Guohui
Liu, Cong
Tao, Youqi
Xie, Jingfei
Lu, Ying
Fang, Xianyang
Luo, Feng
Zhang, Shengnan
Long, Jiangang
Sun, Xiaoou
Zhao, Jiawei
Xie, Jingjing
Diao, Jiajie
Author_xml – sequence: 1
  givenname: Youqi
  surname: Tao
  fullname: Tao, Youqi
  organization: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
– sequence: 2
  givenname: Jingfei
  surname: Xie
  fullname: Xie, Jingfei
  organization: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
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  givenname: Qinglu
  surname: Zhong
  fullname: Zhong, Qinglu
  organization: University of the Chinese Academy of Sciences, Beijing, China
– sequence: 4
  givenname: Yongyao
  surname: Wang
  fullname: Wang, Yongyao
  organization: Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, China
– sequence: 5
  givenname: Shengnan
  orcidid: 0000-0003-1051-7196
  surname: Zhang
  fullname: Zhang, Shengnan
  organization: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
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  surname: Luo
  fullname: Luo, Feng
  organization: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
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  fullname: Wen, Fengcai
  organization: School of Life Science and Technology, ShanghaiTech University, Shanghai, China
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  surname: Xie
  fullname: Xie, Jingjing
  organization: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
– sequence: 9
  givenname: Jiawei
  orcidid: 0000-0002-0582-2105
  surname: Zhao
  fullname: Zhao, Jiawei
  organization: Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing, China
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  surname: Sun
  fullname: Sun, Xiaoou
  organization: Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing, China
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  givenname: Houfang
  surname: Long
  fullname: Long, Houfang
  organization: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
– sequence: 12
  givenname: Junfeng
  surname: Ma
  fullname: Ma, Junfeng
  organization: Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing, China
– sequence: 13
  givenname: Qian
  orcidid: 0000-0002-9187-4277
  surname: Zhang
  fullname: Zhang, Qian
  organization: School of Life Science and Technology, ShanghaiTech University, Shanghai, China
– sequence: 14
  givenname: Jiangang
  surname: Long
  fullname: Long, Jiangang
  organization: Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, China
– sequence: 15
  givenname: Xianyang
  orcidid: 0000-0001-9432-9736
  surname: Fang
  fullname: Fang, Xianyang
  organization: Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing, China
– sequence: 16
  givenname: Ying
  surname: Lu
  fullname: Lu, Ying
  organization: University of the Chinese Academy of Sciences, Beijing, China
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  givenname: Dan
  surname: Li
  fullname: Li, Dan
  organization: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
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  givenname: Ming
  surname: Li
  fullname: Li, Ming
  organization: University of the Chinese Academy of Sciences, Beijing, China
– sequence: 19
  givenname: Jidong
  surname: Zhu
  fullname: Zhu, Jidong
  organization: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
– sequence: 20
  givenname: Bo
  orcidid: 0000-0002-4590-7795
  surname: Sun
  fullname: Sun, Bo
  organization: School of Life Science and Technology, ShanghaiTech University, Shanghai, China
– sequence: 21
  givenname: Guohui
  surname: Li
  fullname: Li, Guohui
  email: ghli@dicp.ac.cn
  organization: University of the Chinese Academy of Sciences, Beijing, China
– sequence: 22
  givenname: Jiajie
  surname: Diao
  fullname: Diao, Jiajie
  email: jiajie.diao@uc.edu
  organization: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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  givenname: Cong
  orcidid: 0000-0003-3425-6672
  surname: Liu
  fullname: Liu, Cong
  email: liulab@sioc.ac.cn
  organization: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
BackLink https://www.ncbi.nlm.nih.gov/pubmed/33722610$$D View this record in MEDLINE/PubMed
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Keywords single-molecule biophysics
TDP
IRS-1
ABMD
fluorescence resonance energy transfer
tyrosine-protein phosphatase (tyrosine phosphatase)
allosteric regulation
smFRET
conformational change
TIRF
SAXS
DiFMUP
MD
TCEP
fluorescence resonance energy transfer (FRET)
Language English
License This is an open access article under the CC BY-NC-ND license.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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These authors contributed equally to this work.
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Snippet The protein tyrosine phosphatase SHP2 mediates multiple signal transductions in various cellular pathways, controlled by a variety of upstream inputs. SHP2...
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SubjectTerms allosteric regulation
conformational change
fluorescence resonance energy transfer
single-molecule biophysics
tyrosine-protein phosphatase (tyrosine phosphatase)
Title A novel partially open state of SHP2 points to a “multiple gear” regulation mechanism
URI https://dx.doi.org/10.1016/j.jbc.2021.100538
https://www.ncbi.nlm.nih.gov/pubmed/33722610
https://search.proquest.com/docview/2501848838
https://pubmed.ncbi.nlm.nih.gov/PMC8054191
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