title: NMR Characterization of Information Flow and Allosteric Communities in the MAP Kinase p38γ.
abstract: The intramolecular network structure of a protein provides valuable insights into allosteric sites and communication pathways. However, a straightforward method to comprehensively map and characterize these pathways is not currently available. Here we present an approach to characterize intramolecular network structure using NMR chemical shift perturbations. We apply the method to the mitogen activated protein kinase (MAPK) p38γ. p38γ contains allosteric sites that are conserved among eukaryotic kinases as well as unique to the MAPK family. How these regulatory sites communicate with catalytic residues is not well understood. Using our method, we observe and characterize for the first time information flux between regulatory sites through a conserved kinase infrastructure. This network is accessed, reinforced, and broken in various states of p38γ, reflecting the functional state of the protein. We demonstrate that the approach detects critical junctions in the network corresponding to biologically significant allosteric sites and pathways.
authors.affiliation: Department of Integrative Structural and Computational Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037 California, United States.
authors.forename: Phillip C
authors.initials: PC
authors.lastname: Aoto
authors.affiliation: Department of Integrative Structural and Computational Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037 California, United States.
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Martin
authors.affiliation: Department of Integrative Structural and Computational Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037 California, United States.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Wright
mesh_terms: D000494:Allosteric Regulation; D006801:Humans; D048291:Mitogen-Activated Protein Kinase 12 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D000072417:Protein Domains
chemical_list: D048291:Mitogen-Activated Protein Kinase 12