How mitogen-activated protein kinases recognize and phosphorylate their targets: A QM/MM study

Mitogen-activated protein kinase (MAPK) signaling pathways play an essential role in the transduction of environmental stimuli to the nucleus, thereby regulating a variety of cellular processes, including cell proliferation, differentiation, and programmed cell death. The components of the MAPK extr...

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Autor principal:	Turjanski, Adrián Gustavo
Publicado:	2009
Materias:	Activated proteins Active site Cancer therapy Catalytic base Cellular process Complex structure Environmental stimuli Extracellular Human cancer Kinase activity Mitogen activated protein kinase Molecular events One step Phospho-transfer Phosphoryl transfer Phosphorylation reactions Programmed cell deaths Proline residues Reaction mechanism Signaling pathways Transition state Amines Cell death Cell membranes Cell proliferation Enzyme activity Molecular mechanics Targets magnesium mitogen activated protein kinase mitogen activated protein kinase 1 proline serine threonine peptide article catalysis enzyme phosphorylation molecular mechanics molecular recognition protein analysis protein function protein interaction quantum mechanics chemical model chemical structure chemistry computer simulation conformation enzyme active site metabolism phosphorylation quantum theory synthesis Catalysis Catalytic Domain Computer Simulation Mitogen-Activated Protein Kinases Models, Chemical Models, Molecular Molecular Conformation Peptides Phosphorylation Quantum Theory
Acceso en línea:	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00027863_v131_n17_p6141_Turjanski http://hdl.handle.net/20.500.12110/paper_00027863_v131_n17_p6141_Turjanski
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	paper:paper_00027863_v131_n17_p6141_Turjanski
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spelling	paper:paper_00027863_v131_n17_p6141_Turjanski2023-06-08T14:22:45Z How mitogen-activated protein kinases recognize and phosphorylate their targets: A QM/MM study Turjanski, Adrián Gustavo Activated proteins Active site Cancer therapy Catalytic base Cellular process Complex structure Environmental stimuli Extracellular Human cancer Kinase activity Mitogen activated protein kinase Molecular events One step Phospho-transfer Phosphoryl transfer Phosphorylation reactions Programmed cell deaths Proline residues Reaction mechanism Signaling pathways Transition state Amines Cell death Cell membranes Cell proliferation Enzyme activity Molecular mechanics Targets magnesium mitogen activated protein kinase mitogen activated protein kinase 1 proline serine threonine peptide article catalysis enzyme phosphorylation molecular mechanics molecular recognition protein analysis protein function protein interaction quantum mechanics chemical model chemical structure chemistry computer simulation conformation enzyme active site metabolism phosphorylation quantum theory synthesis Catalysis Catalytic Domain Computer Simulation Mitogen-Activated Protein Kinases Models, Chemical Models, Molecular Molecular Conformation Peptides Phosphorylation Quantum Theory Mitogen-activated protein kinase (MAPK) signaling pathways play an essential role in the transduction of environmental stimuli to the nucleus, thereby regulating a variety of cellular processes, including cell proliferation, differentiation, and programmed cell death. The components of the MAPK extracellular activated protein kinase (ERK) cascade represent attractive targets for cancer therapy, as their aberrant activation is a frequent event among highly prevalent human cancers. To understand how MAPKs recognize and phosphorylate their targets is key to unravel their function. However, these events are still poorly understood because of the lack of complex structures of MAPKs with their bound targets in the active site. Here we have modeled the interaction of ERK with a target peptide and analyzed the specificity toward Ser/Thr-Pro motifs. By using a quantum mechanics/molecular mechanics (QM/MM) approach, we propose a mechanism for the phosphoryl transfer catalyzed by ERK that offers new insights into MAPK function. Our results suggest that (1) the proline residue has a role in both specificity and phospho transfer efficiency, (2) the reaction occurs in one step, with ERK2 Asp 147 acting as the catalytic base, (3) a conserved Lys in the kinase superfamily that is usually mutated to check kinase activity strongly stabilizes the transition state, and (4) the reaction mechanism is similar with either one or two Mg 2+ ions in the active site. Taken together, our results provide a detailed description of the molecular events involved in the phosphorylation reaction catalyzed by MAPK and contribute to the general understanding of kinase activity. © 2009 American Chemical Society. Fil:Turjanski, A.G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2009 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00027863_v131_n17_p6141_Turjanski http://hdl.handle.net/20.500.12110/paper_00027863_v131_n17_p6141_Turjanski
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	Activated proteins Active site Cancer therapy Catalytic base Cellular process Complex structure Environmental stimuli Extracellular Human cancer Kinase activity Mitogen activated protein kinase Molecular events One step Phospho-transfer Phosphoryl transfer Phosphorylation reactions Programmed cell deaths Proline residues Reaction mechanism Signaling pathways Transition state Amines Cell death Cell membranes Cell proliferation Enzyme activity Molecular mechanics Targets magnesium mitogen activated protein kinase mitogen activated protein kinase 1 proline serine threonine peptide article catalysis enzyme phosphorylation molecular mechanics molecular recognition protein analysis protein function protein interaction quantum mechanics chemical model chemical structure chemistry computer simulation conformation enzyme active site metabolism phosphorylation quantum theory synthesis Catalysis Catalytic Domain Computer Simulation Mitogen-Activated Protein Kinases Models, Chemical Models, Molecular Molecular Conformation Peptides Phosphorylation Quantum Theory
spellingShingle	Activated proteins Active site Cancer therapy Catalytic base Cellular process Complex structure Environmental stimuli Extracellular Human cancer Kinase activity Mitogen activated protein kinase Molecular events One step Phospho-transfer Phosphoryl transfer Phosphorylation reactions Programmed cell deaths Proline residues Reaction mechanism Signaling pathways Transition state Amines Cell death Cell membranes Cell proliferation Enzyme activity Molecular mechanics Targets magnesium mitogen activated protein kinase mitogen activated protein kinase 1 proline serine threonine peptide article catalysis enzyme phosphorylation molecular mechanics molecular recognition protein analysis protein function protein interaction quantum mechanics chemical model chemical structure chemistry computer simulation conformation enzyme active site metabolism phosphorylation quantum theory synthesis Catalysis Catalytic Domain Computer Simulation Mitogen-Activated Protein Kinases Models, Chemical Models, Molecular Molecular Conformation Peptides Phosphorylation Quantum Theory Turjanski, Adrián Gustavo How mitogen-activated protein kinases recognize and phosphorylate their targets: A QM/MM study
topic_facet	Activated proteins Active site Cancer therapy Catalytic base Cellular process Complex structure Environmental stimuli Extracellular Human cancer Kinase activity Mitogen activated protein kinase Molecular events One step Phospho-transfer Phosphoryl transfer Phosphorylation reactions Programmed cell deaths Proline residues Reaction mechanism Signaling pathways Transition state Amines Cell death Cell membranes Cell proliferation Enzyme activity Molecular mechanics Targets magnesium mitogen activated protein kinase mitogen activated protein kinase 1 proline serine threonine peptide article catalysis enzyme phosphorylation molecular mechanics molecular recognition protein analysis protein function protein interaction quantum mechanics chemical model chemical structure chemistry computer simulation conformation enzyme active site metabolism phosphorylation quantum theory synthesis Catalysis Catalytic Domain Computer Simulation Mitogen-Activated Protein Kinases Models, Chemical Models, Molecular Molecular Conformation Peptides Phosphorylation Quantum Theory
description	Mitogen-activated protein kinase (MAPK) signaling pathways play an essential role in the transduction of environmental stimuli to the nucleus, thereby regulating a variety of cellular processes, including cell proliferation, differentiation, and programmed cell death. The components of the MAPK extracellular activated protein kinase (ERK) cascade represent attractive targets for cancer therapy, as their aberrant activation is a frequent event among highly prevalent human cancers. To understand how MAPKs recognize and phosphorylate their targets is key to unravel their function. However, these events are still poorly understood because of the lack of complex structures of MAPKs with their bound targets in the active site. Here we have modeled the interaction of ERK with a target peptide and analyzed the specificity toward Ser/Thr-Pro motifs. By using a quantum mechanics/molecular mechanics (QM/MM) approach, we propose a mechanism for the phosphoryl transfer catalyzed by ERK that offers new insights into MAPK function. Our results suggest that (1) the proline residue has a role in both specificity and phospho transfer efficiency, (2) the reaction occurs in one step, with ERK2 Asp 147 acting as the catalytic base, (3) a conserved Lys in the kinase superfamily that is usually mutated to check kinase activity strongly stabilizes the transition state, and (4) the reaction mechanism is similar with either one or two Mg 2+ ions in the active site. Taken together, our results provide a detailed description of the molecular events involved in the phosphorylation reaction catalyzed by MAPK and contribute to the general understanding of kinase activity. © 2009 American Chemical Society.
author	Turjanski, Adrián Gustavo
author_facet	Turjanski, Adrián Gustavo
author_sort	Turjanski, Adrián Gustavo
title	How mitogen-activated protein kinases recognize and phosphorylate their targets: A QM/MM study
title_short	How mitogen-activated protein kinases recognize and phosphorylate their targets: A QM/MM study
title_full	How mitogen-activated protein kinases recognize and phosphorylate their targets: A QM/MM study
title_fullStr	How mitogen-activated protein kinases recognize and phosphorylate their targets: A QM/MM study
title_full_unstemmed	How mitogen-activated protein kinases recognize and phosphorylate their targets: A QM/MM study
title_sort	how mitogen-activated protein kinases recognize and phosphorylate their targets: a qm/mm study
publishDate	2009
url	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00027863_v131_n17_p6141_Turjanski http://hdl.handle.net/20.500.12110/paper_00027863_v131_n17_p6141_Turjanski
work_keys_str_mv	AT turjanskiadriangustavo howmitogenactivatedproteinkinasesrecognizeandphosphorylatetheirtargetsaqmmmstudy
_version_	1768544109974257664

How mitogen-activated protein kinases recognize and phosphorylate their targets: A QM/MM study

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