Artículo

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" (2011) Biochemistry. 50(8):1384-1395
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Abstract:

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.

Registro:

Documento: Artículo
Título:P38γ activation triggers dynamical changes in allosteric docking sites
Autor:Rodriguez Limardo, R.G.; Ferreiro, D.N.; Roitberg, A.E.; Marti, M.A.; Turjanski, A.G.
Filiación:Departamento de Química Inorgánica, Analítica y Química Física, INQUIMAE-CONICET, Facultad de Ciencias Exactas y Naturales, Ciudad Universitaria, Buenos Aires C1428EHA, Argentina
Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires C1428EHA, Argentina
Department of Chemistry, University of Florida, Gainesville, FL 32611-8435, United States
Palabras clave: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
Año:2011
Volumen:50
Número:8
Página de inicio:1384
Página de fin:1395
DOI: http://dx.doi.org/10.1021/bi1007518
Título revista:Biochemistry
Título revista abreviado:Biochemistry
ISSN:00062960
CODEN:BICHA
CAS:adenosine triphosphate, 15237-44-2, 56-65-5, 987-65-5; Adenosine Triphosphate, 56-65-5; Mitogen-Activated Protein Kinase 12, 2.7.1.-
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00062960_v50_n8_p1384_RodriguezLimardo

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Citas:

---------- APA ----------
Rodriguez Limardo, R.G., Ferreiro, D.N., Roitberg, A.E., Marti, M.A. & Turjanski, A.G. (2011) . P38γ activation triggers dynamical changes in allosteric docking sites. Biochemistry, 50(8), 1384-1395.
http://dx.doi.org/10.1021/bi1007518
---------- CHICAGO ----------
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" . Biochemistry 50, no. 8 (2011) : 1384-1395.
http://dx.doi.org/10.1021/bi1007518
---------- MLA ----------
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" . Biochemistry, vol. 50, no. 8, 2011, pp. 1384-1395.
http://dx.doi.org/10.1021/bi1007518
---------- VANCOUVER ----------
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. Biochemistry. 2011;50(8):1384-1395.
http://dx.doi.org/10.1021/bi1007518