Molecular mechanism of ERK dephosphorylation by striatal-enriched protein tyrosine phosphatase

Rong Li, Di Dong Xie, Jun Hong Dong, Hui Li, Kang Shuai Li, Jing Su, Lai Zhong Chen, Yun Fei Xu, Hong Mei Wang, Zheng Gong, Guo Ying Cui, Xiao Yu, Kai Wang, Wei Yao, Tao Xin, Min Yong Li, Kun Hong Xiao, Xiao Fei An, Yuqing Huo, Zhi Gang XuJin Peng Sun, Qi Pang

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Striatal-enriched tyrosine phosphatase (STEP) is an important regulator of neuronal synaptic plasticity, and its abnormal level or activity contributes to cognitive disorders. One crucial downstream effector and direct substrate of STEP is extracellular signal-regulated protein kinase (ERK), which has important functions in spine stabilisation and action potential transmission. The inhibition of STEP activity toward phospho-ERK has the potential to treat neuronal diseases, but the detailed mechanism underlying the dephosphorylation of phospho-ERK by STEP is not known. Therefore, we examined STEP activity toward para-nitrophenyl phosphate, phospho-tyrosine-containing peptides, and the full-length phospho-ERK protein using STEP mutants with different structural features. STEP was found to be a highly efficient ERK tyrosine phosphatase that required both its N-terminal regulatory region and key residues in its active site. Specifically, both kinase interaction motif (KIM) and kinase-specific sequence of STEP were required for ERK interaction. In addition to the N-terminal kinase-specific sequence region, S245, hydrophobic residues L249/L251, and basic residues R242/R243 located in the KIM region were important in controlling STEP activity toward phospho-ERK. Further kinetic experiments revealed subtle structural differences between STEP and HePTP that affected the interactions of their KIMs with ERK. Moreover, STEP recognised specific positions of a phospho-ERK peptide sequence through its active site, and the contact of STEP F311 with phospho-ERK V205 and T207 were crucial interactions. Taken together, our results not only provide the information for interactions between ERK and STEP, but will also help in the development of specific strategies to target STEP-ERK recognition, which could serve as a potential therapy for neurological disorders. Regulation of phospho-ERK by STEP underlies important neuronal activities. A detailed enzymologic characterisation and cellular studies of STEP revealed that specific residues in KIM and active site mediated ERK recognition. Structural differences between the KIM-ERK interfaces and the active site among different ERK phosphatases could be targeted to develop specific STEP inhibitor, which has therapeutic potential for neurological disorders. PKA, protein kinase A & NGF, nerve growth factor. Regulation of phospho-ERK by STEP underlies important neuronal activities. A detailed enzymologic characterisation and cellular studies of STEP revealed that specific residues in KIM and active site mediated ERK recognition. Structural differences between the KIM-ERK interfaces and the active site among different ERK phosphatases could be targeted to develop specific STEP inhibitor, which has therapeutic potential for neurological disorders. PKA, protein kinase A & NGF, nerve growth factor.

Original languageEnglish (US)
Pages (from-to)315-329
Number of pages15
JournalJournal of Neurochemistry
Volume128
Issue number2
DOIs
StatePublished - Jan 1 2014

Fingerprint

Corpus Striatum
Protein Tyrosine Phosphatases
Phosphoric Monoester Hydrolases
Tyrosine
Phosphotransferases
Catalytic Domain
Nerve Growth Factor
Nervous System Diseases
Neuronal Plasticity
Cyclic AMP-Dependent Protein Kinases

Keywords

  • ERK
  • neurological disorders
  • phosphatase
  • phosphorylation
  • striatal enriched tyrosine phosphatases
  • synaptic plasticity

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Li, R., Xie, D. D., Dong, J. H., Li, H., Li, K. S., Su, J., ... Pang, Q. (2014). Molecular mechanism of ERK dephosphorylation by striatal-enriched protein tyrosine phosphatase. Journal of Neurochemistry, 128(2), 315-329. https://doi.org/10.1111/jnc.12463

Molecular mechanism of ERK dephosphorylation by striatal-enriched protein tyrosine phosphatase. / Li, Rong; Xie, Di Dong; Dong, Jun Hong; Li, Hui; Li, Kang Shuai; Su, Jing; Chen, Lai Zhong; Xu, Yun Fei; Wang, Hong Mei; Gong, Zheng; Cui, Guo Ying; Yu, Xiao; Wang, Kai; Yao, Wei; Xin, Tao; Li, Min Yong; Xiao, Kun Hong; An, Xiao Fei; Huo, Yuqing; Xu, Zhi Gang; Sun, Jin Peng; Pang, Qi.

In: Journal of Neurochemistry, Vol. 128, No. 2, 01.01.2014, p. 315-329.

Research output: Contribution to journalArticle

Li, R, Xie, DD, Dong, JH, Li, H, Li, KS, Su, J, Chen, LZ, Xu, YF, Wang, HM, Gong, Z, Cui, GY, Yu, X, Wang, K, Yao, W, Xin, T, Li, MY, Xiao, KH, An, XF, Huo, Y, Xu, ZG, Sun, JP & Pang, Q 2014, 'Molecular mechanism of ERK dephosphorylation by striatal-enriched protein tyrosine phosphatase', Journal of Neurochemistry, vol. 128, no. 2, pp. 315-329. https://doi.org/10.1111/jnc.12463
Li, Rong ; Xie, Di Dong ; Dong, Jun Hong ; Li, Hui ; Li, Kang Shuai ; Su, Jing ; Chen, Lai Zhong ; Xu, Yun Fei ; Wang, Hong Mei ; Gong, Zheng ; Cui, Guo Ying ; Yu, Xiao ; Wang, Kai ; Yao, Wei ; Xin, Tao ; Li, Min Yong ; Xiao, Kun Hong ; An, Xiao Fei ; Huo, Yuqing ; Xu, Zhi Gang ; Sun, Jin Peng ; Pang, Qi. / Molecular mechanism of ERK dephosphorylation by striatal-enriched protein tyrosine phosphatase. In: Journal of Neurochemistry. 2014 ; Vol. 128, No. 2. pp. 315-329.
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AU - Xie, Di Dong

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AU - Li, Hui

AU - Li, Kang Shuai

AU - Su, Jing

AU - Chen, Lai Zhong

AU - Xu, Yun Fei

AU - Wang, Hong Mei

AU - Gong, Zheng

AU - Cui, Guo Ying

AU - Yu, Xiao

AU - Wang, Kai

AU - Yao, Wei

AU - Xin, Tao

AU - Li, Min Yong

AU - Xiao, Kun Hong

AU - An, Xiao Fei

AU - Huo, Yuqing

AU - Xu, Zhi Gang

AU - Sun, Jin Peng

AU - Pang, Qi

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N2 - Striatal-enriched tyrosine phosphatase (STEP) is an important regulator of neuronal synaptic plasticity, and its abnormal level or activity contributes to cognitive disorders. One crucial downstream effector and direct substrate of STEP is extracellular signal-regulated protein kinase (ERK), which has important functions in spine stabilisation and action potential transmission. The inhibition of STEP activity toward phospho-ERK has the potential to treat neuronal diseases, but the detailed mechanism underlying the dephosphorylation of phospho-ERK by STEP is not known. Therefore, we examined STEP activity toward para-nitrophenyl phosphate, phospho-tyrosine-containing peptides, and the full-length phospho-ERK protein using STEP mutants with different structural features. STEP was found to be a highly efficient ERK tyrosine phosphatase that required both its N-terminal regulatory region and key residues in its active site. Specifically, both kinase interaction motif (KIM) and kinase-specific sequence of STEP were required for ERK interaction. In addition to the N-terminal kinase-specific sequence region, S245, hydrophobic residues L249/L251, and basic residues R242/R243 located in the KIM region were important in controlling STEP activity toward phospho-ERK. Further kinetic experiments revealed subtle structural differences between STEP and HePTP that affected the interactions of their KIMs with ERK. Moreover, STEP recognised specific positions of a phospho-ERK peptide sequence through its active site, and the contact of STEP F311 with phospho-ERK V205 and T207 were crucial interactions. Taken together, our results not only provide the information for interactions between ERK and STEP, but will also help in the development of specific strategies to target STEP-ERK recognition, which could serve as a potential therapy for neurological disorders. Regulation of phospho-ERK by STEP underlies important neuronal activities. A detailed enzymologic characterisation and cellular studies of STEP revealed that specific residues in KIM and active site mediated ERK recognition. Structural differences between the KIM-ERK interfaces and the active site among different ERK phosphatases could be targeted to develop specific STEP inhibitor, which has therapeutic potential for neurological disorders. PKA, protein kinase A & NGF, nerve growth factor. Regulation of phospho-ERK by STEP underlies important neuronal activities. A detailed enzymologic characterisation and cellular studies of STEP revealed that specific residues in KIM and active site mediated ERK recognition. Structural differences between the KIM-ERK interfaces and the active site among different ERK phosphatases could be targeted to develop specific STEP inhibitor, which has therapeutic potential for neurological disorders. PKA, protein kinase A & NGF, nerve growth factor.

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