title: A simple electrostatic switch important in the activation of type I protein kinase A by cyclic AMP.
abstract: Cyclic AMP activates protein kinase A by binding to an inhibitory regulatory (R) subunit and releasing inhibition of the catalytic (C) subunit. Even though crystal structures of regulatory and catalytic subunits have been solved, the precise molecular mechanism by which cyclic AMP activates the kinase remains unknown. The dynamic properties of the cAMP binding domain in the absence of cAMP or C-subunit are also unknown. Here we report molecular-dynamics simulations and mutational studies of the RIalpha R-subunit that identify the C-helix as a highly dynamic switch which relays cAMP binding to the helical C-subunit binding regions. Furthermore, we identify an important salt bridge which links cAMP binding directly to the C-helix that is necessary for normal activation. Additional mutations show that a hydrophobic "hinge" region is not as critical for the cross-talk in PKA as it is in the homologous EPAC protein, illustrating how cAMP can control diverse functions using the evolutionarily conserved cAMP-binding domains.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, San Diego, CA 92037, USA.
authors.forename: Dominico
authors.initials: D
authors.lastname: Vigil
authors.forename: Jung-Hsin
authors.initials: JH
authors.lastname: Lin
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Sotriffer
authors.forename: Juniper K
authors.initials: JK
authors.lastname: Pennypacker
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
authors.forename: Susan S
authors.initials: SS
authors.lastname: Taylor
mesh_terms: D000818:Animals; D003198:Computer Simulation; D000242:Cyclic AMP / Q000737:chemistry / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D006358:Hot Temperature; D008956:Models, Chemical; D008958:Models, Molecular; D011489:Protein Denaturation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D055672:Static Electricity
chemical_list: D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases