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Abstract:

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.

Registro:

Documento: Artículo
Título:How mitogen-activated protein kinases recognize and phosphorylate their targets: A QM/MM study
Autor:Turjanski, A.G.; Hummer, G.; Gutkind, J.S.
Filiación:Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, Laboratory of Chemical Physics, Bethesda, MD 20892-0520, United States
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520, United States
Departamento de Química Inorgánica, Analítica y Química Física e INQUIMAE, Buenos Aires, Argentina
Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, UBA, Buenos Aires, Argentina
Palabras clave: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
Año:2009
Volumen:131
Número:17
Página de inicio:6141
Página de fin:6148
DOI: http://dx.doi.org/10.1021/ja8071995
Título revista:Journal of the American Chemical Society
Título revista abreviado:J. Am. Chem. Soc.
ISSN:00027863
CODEN:JACSA
CAS:magnesium, 7439-95-4; mitogen activated protein kinase, 142243-02-5; mitogen activated protein kinase 1, 137632-08-7; proline, 147-85-3, 7005-20-1; serine, 56-45-1, 6898-95-9; threonine, 36676-50-3, 72-19-5; Mitogen-Activated Protein Kinases, 2.7.11.24; Peptides
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00027863_v131_n17_p6141_Turjanski

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Citas:

---------- APA ----------
Turjanski, A.G., Hummer, G. & Gutkind, J.S. (2009) . How mitogen-activated protein kinases recognize and phosphorylate their targets: A QM/MM study. Journal of the American Chemical Society, 131(17), 6141-6148.
http://dx.doi.org/10.1021/ja8071995
---------- CHICAGO ----------
Turjanski, A.G., Hummer, G., Gutkind, J.S. "How mitogen-activated protein kinases recognize and phosphorylate their targets: A QM/MM study" . Journal of the American Chemical Society 131, no. 17 (2009) : 6141-6148.
http://dx.doi.org/10.1021/ja8071995
---------- MLA ----------
Turjanski, A.G., Hummer, G., Gutkind, J.S. "How mitogen-activated protein kinases recognize and phosphorylate their targets: A QM/MM study" . Journal of the American Chemical Society, vol. 131, no. 17, 2009, pp. 6141-6148.
http://dx.doi.org/10.1021/ja8071995
---------- VANCOUVER ----------
Turjanski, A.G., Hummer, G., Gutkind, J.S. How mitogen-activated protein kinases recognize and phosphorylate their targets: A QM/MM study. J. Am. Chem. Soc. 2009;131(17):6141-6148.
http://dx.doi.org/10.1021/ja8071995