P38γ activation triggers dynamical changes in allosteric docking sites

Mitogen-activated protein kinases (MAPKs) are serine-threonine kinases that participate in signal transduction pathways. p38 MAPKs have four isoforms (p38β, p38β, p38γ, and p38δ) which are involved in multiple cellular functions such as proliferation, differentiation, survival, and migration. MAPK k...

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Autores principales:	Rodriguez Limardo, R.G., Ferreiro, D.N., Roitberg, A.E., Marti, M.A., Turjanski, A.G.
Formato:	JOUR
Materias:	Activation loops Active site ATP binding Bound state Catalytic activity Conformational change Correlated dynamics Docking sites Dynamical fluctuations Isoforms Key factors MD simulation Mitogen activated protein kinase Molecular dynamics techniques Multiple cellular functions Protein domains Protein dynamics Protein-protein interactions Signal transduction pathways Signaling networks Threonine kinase Two domains Amino acids Binding energy Docking Dynamics Enzymes Molecular dynamics Phosphorylation Plasticity Signal transduction Signaling Catalyst activity adenosine triphosphate mitogen activated protein kinase p38 mitogen activated protein kinase p38 gamma unclassified drug article binding site conformational transition enzyme activation enzyme active site enzyme conformation enzyme phosphorylation molecular dynamics motion priority journal protein domain protein protein interaction simulation Adenosine Triphosphate Allosteric Regulation Enzyme Activation Mitogen-Activated Protein Kinase 12 Molecular Dynamics Simulation Movement Protein Structure, Secondary Protein Structure, Tertiary
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_00062960_v50_n8_p1384_RodriguezLimardo
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	todo:paper_00062960_v50_n8_p1384_RodriguezLimardo
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spelling	todo:paper_00062960_v50_n8_p1384_RodriguezLimardo2023-10-03T14:04:33Z P38γ activation triggers dynamical changes in allosteric docking sites Rodriguez Limardo, R.G. Ferreiro, D.N. Roitberg, A.E. Marti, M.A. Turjanski, A.G. Activation loops Active site ATP binding Bound state Catalytic activity Conformational change Correlated dynamics Docking sites Dynamical fluctuations Isoforms Key factors MD simulation Mitogen activated protein kinase Molecular dynamics techniques Multiple cellular functions Protein domains Protein dynamics Protein-protein interactions Signal transduction pathways Signaling networks Threonine kinase Two domains Amino acids Binding energy Docking Dynamics Enzymes Molecular dynamics Phosphorylation Plasticity Signal transduction Signaling Catalyst activity adenosine triphosphate mitogen activated protein kinase p38 mitogen activated protein kinase p38 gamma unclassified drug article binding site conformational transition enzyme activation enzyme active site enzyme conformation enzyme phosphorylation molecular dynamics motion priority journal protein domain protein protein interaction simulation Adenosine Triphosphate Allosteric Regulation Enzyme Activation Mitogen-Activated Protein Kinase 12 Molecular Dynamics Simulation Movement Phosphorylation Protein Structure, Secondary Protein Structure, Tertiary Mitogen-activated protein kinases (MAPKs) are serine-threonine kinases that participate in signal transduction pathways. p38 MAPKs have four isoforms (p38β, p38β, p38γ, and p38δ) which are involved in multiple cellular functions such as proliferation, differentiation, survival, and migration. MAPK kinases phosphorylate p38s in the dual-phosphorylation motif, Thr-Gly-Tyr, located in their activation loop, which induces a conformational change that increases ATP binding affinity and catalytic activity. Several works have proposed that MAPK dynamics is a key factor in determining their function. However, we still do not understand the dynamical changes that lead to MAPK activation. In this work we have used molecular dynamics techniques to study the dynamical changes associated with p38γ activation, the only fully active MAPK crystallized so far. We performed MD simulations of p38γ in three different states, fully active with ATP, active without ATP, and inactive. We found that the dynamical fluctuations of the docking sites, important for protein-protein interactions, are regulated allosterically by changes in the active site. Interestingly, in the phosphorylated and ATP-bound states the whole protein dynamics lead to concerted motions of whole protein domains in contrast to the inactive state. The binding/unbinding of ATP participates in the reorientation of the two domains and in the regulation of protein plasticity. Our study shows that beyond the conformational changes associated with MAPK activation their correlated dynamics are highly regulated by phosphorylation and ATP binding. This means that MAPK plasticity may have a role in their catalytic activity, specificity, and protein-protein interactions and, therefore, in the outcome of the signaling network. © 2011 American Chemical Society. Fil:Rodriguez Limardo, R.G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Ferreiro, D.N. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Marti, M.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Turjanski, A.G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00062960_v50_n8_p1384_RodriguezLimardo
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	Activation loops Active site ATP binding Bound state Catalytic activity Conformational change Correlated dynamics Docking sites Dynamical fluctuations Isoforms Key factors MD simulation Mitogen activated protein kinase Molecular dynamics techniques Multiple cellular functions Protein domains Protein dynamics Protein-protein interactions Signal transduction pathways Signaling networks Threonine kinase Two domains Amino acids Binding energy Docking Dynamics Enzymes Molecular dynamics Phosphorylation Plasticity Signal transduction Signaling Catalyst activity adenosine triphosphate mitogen activated protein kinase p38 mitogen activated protein kinase p38 gamma unclassified drug article binding site conformational transition enzyme activation enzyme active site enzyme conformation enzyme phosphorylation molecular dynamics motion priority journal protein domain protein protein interaction simulation Adenosine Triphosphate Allosteric Regulation Enzyme Activation Mitogen-Activated Protein Kinase 12 Molecular Dynamics Simulation Movement Phosphorylation Protein Structure, Secondary Protein Structure, Tertiary
spellingShingle	Activation loops Active site ATP binding Bound state Catalytic activity Conformational change Correlated dynamics Docking sites Dynamical fluctuations Isoforms Key factors MD simulation Mitogen activated protein kinase Molecular dynamics techniques Multiple cellular functions Protein domains Protein dynamics Protein-protein interactions Signal transduction pathways Signaling networks Threonine kinase Two domains Amino acids Binding energy Docking Dynamics Enzymes Molecular dynamics Phosphorylation Plasticity Signal transduction Signaling Catalyst activity adenosine triphosphate mitogen activated protein kinase p38 mitogen activated protein kinase p38 gamma unclassified drug article binding site conformational transition enzyme activation enzyme active site enzyme conformation enzyme phosphorylation molecular dynamics motion priority journal protein domain protein protein interaction simulation Adenosine Triphosphate Allosteric Regulation Enzyme Activation Mitogen-Activated Protein Kinase 12 Molecular Dynamics Simulation Movement Phosphorylation Protein Structure, Secondary Protein Structure, Tertiary Rodriguez Limardo, R.G. Ferreiro, D.N. Roitberg, A.E. Marti, M.A. Turjanski, A.G. P38γ activation triggers dynamical changes in allosteric docking sites
topic_facet	Activation loops Active site ATP binding Bound state Catalytic activity Conformational change Correlated dynamics Docking sites Dynamical fluctuations Isoforms Key factors MD simulation Mitogen activated protein kinase Molecular dynamics techniques Multiple cellular functions Protein domains Protein dynamics Protein-protein interactions Signal transduction pathways Signaling networks Threonine kinase Two domains Amino acids Binding energy Docking Dynamics Enzymes Molecular dynamics Phosphorylation Plasticity Signal transduction Signaling Catalyst activity adenosine triphosphate mitogen activated protein kinase p38 mitogen activated protein kinase p38 gamma unclassified drug article binding site conformational transition enzyme activation enzyme active site enzyme conformation enzyme phosphorylation molecular dynamics motion priority journal protein domain protein protein interaction simulation Adenosine Triphosphate Allosteric Regulation Enzyme Activation Mitogen-Activated Protein Kinase 12 Molecular Dynamics Simulation Movement Phosphorylation Protein Structure, Secondary Protein Structure, Tertiary
description	Mitogen-activated protein kinases (MAPKs) are serine-threonine kinases that participate in signal transduction pathways. p38 MAPKs have four isoforms (p38β, p38β, p38γ, and p38δ) which are involved in multiple cellular functions such as proliferation, differentiation, survival, and migration. MAPK kinases phosphorylate p38s in the dual-phosphorylation motif, Thr-Gly-Tyr, located in their activation loop, which induces a conformational change that increases ATP binding affinity and catalytic activity. Several works have proposed that MAPK dynamics is a key factor in determining their function. However, we still do not understand the dynamical changes that lead to MAPK activation. In this work we have used molecular dynamics techniques to study the dynamical changes associated with p38γ activation, the only fully active MAPK crystallized so far. We performed MD simulations of p38γ in three different states, fully active with ATP, active without ATP, and inactive. We found that the dynamical fluctuations of the docking sites, important for protein-protein interactions, are regulated allosterically by changes in the active site. Interestingly, in the phosphorylated and ATP-bound states the whole protein dynamics lead to concerted motions of whole protein domains in contrast to the inactive state. The binding/unbinding of ATP participates in the reorientation of the two domains and in the regulation of protein plasticity. Our study shows that beyond the conformational changes associated with MAPK activation their correlated dynamics are highly regulated by phosphorylation and ATP binding. This means that MAPK plasticity may have a role in their catalytic activity, specificity, and protein-protein interactions and, therefore, in the outcome of the signaling network. © 2011 American Chemical Society.
format	JOUR
author	Rodriguez Limardo, R.G. Ferreiro, D.N. Roitberg, A.E. Marti, M.A. Turjanski, A.G.
author_facet	Rodriguez Limardo, R.G. Ferreiro, D.N. Roitberg, A.E. Marti, M.A. Turjanski, A.G.
author_sort	Rodriguez Limardo, R.G.
title	P38γ activation triggers dynamical changes in allosteric docking sites
title_short	P38γ activation triggers dynamical changes in allosteric docking sites
title_full	P38γ activation triggers dynamical changes in allosteric docking sites
title_fullStr	P38γ activation triggers dynamical changes in allosteric docking sites
title_full_unstemmed	P38γ activation triggers dynamical changes in allosteric docking sites
title_sort	p38γ activation triggers dynamical changes in allosteric docking sites
url	http://hdl.handle.net/20.500.12110/paper_00062960_v50_n8_p1384_RodriguezLimardo
work_keys_str_mv	AT rodriguezlimardorg p38gactivationtriggersdynamicalchangesinallostericdockingsites AT ferreirodn p38gactivationtriggersdynamicalchangesinallostericdockingsites AT roitbergae p38gactivationtriggersdynamicalchangesinallostericdockingsites AT martima p38gactivationtriggersdynamicalchangesinallostericdockingsites AT turjanskiag p38gactivationtriggersdynamicalchangesinallostericdockingsites
_version_	1807323929289687040

P38γ activation triggers dynamical changes in allosteric docking sites

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