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Isensee, J.* ; Kaufholz, M.* ; Knape, M.J.* ; Hasenauer, J. ; Hammerich, H.* ; Gonczarowska-Jorge, H.* ; Zahedi, R.P.* ; Schwede, F.* ; Herberg, F.W.* ; Hucho, T.*

PKA-RII subunit phosphorylation precedes activation by cAMP and regulates activity termination.

J. Cell Biol. 217, 2167-2184 (2018)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Type II isoforms of cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA-II) contain a phosphorylatable epitope within the inhibitory domain of RII subunits (pRII) with still unclear function. In vitro, RII phosphorylation occurs in the absence of cAMP, whereas staining of cells with pRII-specific antibodies revealed a cAMP-dependent pattern. In sensory neurons, we found that increased pRII immunoreactivity reflects increased accessibility of the already phosphorylated RII epitope during cAMP-induced opening of the tetrameric RII2:C-2 holoenzyme. Accordingly, induction of pRII by cAMP was sensitive to novel inhibitors of dissociation, whereas blocking catalytic activity was ineffective. Also in vitro, cAMP increased the binding of pRII antibodies to RII2:C-2 holoenzymes. Identification of an antibody specific for the glycine-rich loop of catalytic subunits facing the pRII-epitope confirmed activity-dependent binding with similar kinetics, proving that the reassociation is rapid and precisely controlled. Mechanistic modeling further supported that RII phosphorylation precedes cAMP binding and controls the inactivation by modulating the reassociation involving the coordinated action of phosphodiesterases and phosphatases.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Dependent Protein-kinase; Resonance Energy-transfer; Rabbit Skeletal-muscle; Catalytic Subunit; Enzyme Activation; Sensory Neurons; Transfer Bret; Adenosine 3; A Activity; Dynamics
ISSN (print) / ISBN 0021-9525
e-ISSN 1540-8140
Zeitschrift Journal of Cell Biology, The
Quellenangaben Band: 217, Heft: 6, Seiten: 2167-2184 Artikelnummer: , Supplement: ,
Verlag Rockefeller University Press
Verlagsort 950 Third Ave, 2nd Flr, New York, Ny 10022 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Computational Biology (ICB)