Dynamic activation and regulation of the mitogen-activated protein kinase p38. 2018

Ganesan Senthil Kumar, and Michael W Clarkson, and Micha B A Kunze, and Daniele Granata, and A Joshua Wand, and Kresten Lindorff-Larsen, and Rebecca Page, and Wolfgang Peti
Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721.

Mitogen-activated protein kinases, which include p38, are essential for cell differentiation and autophagy. The current model for p38 activation involves activation-loop phosphorylation with subsequent substrate binding leading to substrate phosphorylation. Despite extensive efforts, the molecular mechanism of activation remains unclear. Here, using NMR spectroscopy, we show how the modulation of protein dynamics across timescales activates p38. We find that activation-loop phosphorylation does not change the average conformation of p38; rather it quenches the loop ps-ns dynamics. We then show that substrate binding to nonphosphorylated and phosphorylated p38 results in uniform µs-ms backbone dynamics at catalytically essential regions and across the entire molecule, respectively. Together, these results show that phosphorylation and substrate binding flatten the energy landscape of the protein, making essential elements of allostery and activation dynamically accessible. The high degree of structural conservation among ser/thr kinases suggests that elements of this mechanism may be conserved across the kinase family.

UI MeSH Term Description Entries
D010766 Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Phosphorylations
D004789 Enzyme Activation Conversion of an inactive form of an enzyme to one possessing metabolic activity. It includes 1, activation by ions (activators); 2, activation by cofactors (coenzymes); and 3, conversion of an enzyme precursor (proenzyme or zymogen) to an active enzyme. Activation, Enzyme,Activations, Enzyme,Enzyme Activations
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000494 Allosteric Regulation The modification of the reactivity of ENZYMES by the binding of effectors to sites (ALLOSTERIC SITES) on the enzymes other than the substrate BINDING SITES. Regulation, Allosteric,Allosteric Regulations,Regulations, Allosteric
D017433 Protein Structure, Secondary The level of protein structure in which regular hydrogen-bond interactions within contiguous stretches of polypeptide chain give rise to ALPHA-HELICES; BETA-STRANDS (which align to form BETA-SHEETS), or other types of coils. This is the first folding level of protein conformation. Secondary Protein Structure,Protein Structures, Secondary,Secondary Protein Structures,Structure, Secondary Protein,Structures, Secondary Protein
D048051 p38 Mitogen-Activated Protein Kinases A mitogen-activated protein kinase subfamily that regulates a variety of cellular processes including CELL GROWTH PROCESSES; CELL DIFFERENTIATION; APOPTOSIS; and cellular responses to INFLAMMATION. The P38 MAP kinases are regulated by CYTOKINE RECEPTORS and can be activated in response to bacterial pathogens. Mitogen-Activated Protein Kinase p38,p38 Mitogen-Activated Protein Kinase,p38 MAP Kinase,p38 MAPK,p38 Protein Kinase,p38 SAPK,MAP Kinase, p38,MAPK, p38,Mitogen Activated Protein Kinase p38,Protein Kinase, p38,p38 Mitogen Activated Protein Kinase,p38 Mitogen Activated Protein Kinases
D056004 Molecular Dynamics Simulation A computer simulation developed to study the motion of molecules over a period of time. Molecular Dynamics Simulations,Molecular Dynamics,Dynamic, Molecular,Dynamics Simulation, Molecular,Dynamics Simulations, Molecular,Dynamics, Molecular,Molecular Dynamic,Simulation, Molecular Dynamics,Simulations, Molecular Dynamics
D019906 Nuclear Magnetic Resonance, Biomolecular NMR spectroscopy on small- to medium-size biological macromolecules. This is often used for structural investigation of proteins and nucleic acids, and often involves more than one isotope. Biomolecular Nuclear Magnetic Resonance,Heteronuclear Nuclear Magnetic Resonance,NMR Spectroscopy, Protein,NMR, Biomolecular,NMR, Heteronuclear,NMR, Multinuclear,Nuclear Magnetic Resonance, Heteronuclear,Protein NMR Spectroscopy,Biomolecular NMR,Heteronuclear NMR,Multinuclear NMR,NMR Spectroscopies, Protein,Protein NMR Spectroscopies,Spectroscopies, Protein NMR,Spectroscopy, Protein NMR

Related Publications

Ganesan Senthil Kumar, and Michael W Clarkson, and Micha B A Kunze, and Daniele Granata, and A Joshua Wand, and Kresten Lindorff-Larsen, and Rebecca Page, and Wolfgang Peti
October 2000, European journal of immunology,
Ganesan Senthil Kumar, and Michael W Clarkson, and Micha B A Kunze, and Daniele Granata, and A Joshua Wand, and Kresten Lindorff-Larsen, and Rebecca Page, and Wolfgang Peti
October 2010, Clinical and experimental immunology,
Ganesan Senthil Kumar, and Michael W Clarkson, and Micha B A Kunze, and Daniele Granata, and A Joshua Wand, and Kresten Lindorff-Larsen, and Rebecca Page, and Wolfgang Peti
January 2015, PloS one,
Ganesan Senthil Kumar, and Michael W Clarkson, and Micha B A Kunze, and Daniele Granata, and A Joshua Wand, and Kresten Lindorff-Larsen, and Rebecca Page, and Wolfgang Peti
October 2019, The Journal of allergy and clinical immunology,
Ganesan Senthil Kumar, and Michael W Clarkson, and Micha B A Kunze, and Daniele Granata, and A Joshua Wand, and Kresten Lindorff-Larsen, and Rebecca Page, and Wolfgang Peti
September 2020, Life sciences,
Ganesan Senthil Kumar, and Michael W Clarkson, and Micha B A Kunze, and Daniele Granata, and A Joshua Wand, and Kresten Lindorff-Larsen, and Rebecca Page, and Wolfgang Peti
August 1998, The American journal of physiology,
Ganesan Senthil Kumar, and Michael W Clarkson, and Micha B A Kunze, and Daniele Granata, and A Joshua Wand, and Kresten Lindorff-Larsen, and Rebecca Page, and Wolfgang Peti
October 2008, Journal of endodontics,
Ganesan Senthil Kumar, and Michael W Clarkson, and Micha B A Kunze, and Daniele Granata, and A Joshua Wand, and Kresten Lindorff-Larsen, and Rebecca Page, and Wolfgang Peti
January 2009, International journal of immunopathology and pharmacology,
Ganesan Senthil Kumar, and Michael W Clarkson, and Micha B A Kunze, and Daniele Granata, and A Joshua Wand, and Kresten Lindorff-Larsen, and Rebecca Page, and Wolfgang Peti
January 2009, Experimental gerontology,
Ganesan Senthil Kumar, and Michael W Clarkson, and Micha B A Kunze, and Daniele Granata, and A Joshua Wand, and Kresten Lindorff-Larsen, and Rebecca Page, and Wolfgang Peti
October 1999, The Journal of biological chemistry,
Copied contents to your clipboard!