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Dynamics of PKA Signaling
Author(s) -
Taylor Susan S.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.309.1
Subject(s) - protein subunit , protein kinase a , phosphorylation , kinase , microbiology and biotechnology , biochemistry , chemistry , gene isoform , biology , gene
The protein kinases represent one of the largest mammalian gene families and regulate in diverse and critical ways most biological processes in all eukaryotic cells. cAMP‐dependent protein kinase (PKA) has served as a prototype for understanding the structure and function of this protein kinase superfamily. The PKA catalytic subunit is assembled into an active conformation by phosphorylation of its activation loop where this single phosphate has profound effects on global structure and function. All active protein kinases share a common architecture that is built upon two hydrophobic spines comprised of residues from both the small (N‐) and large (C‐) lobes. These spines are anchored to the hydrophobic F Helix, which traverses the large helical C‐lobe. The regulatory spine is typically assembled by phosphorylation of the activation loop while the catalytic spine is completed by the adenine ring of ATP. The active kinase then opens and closes as it navigates through the catalytic cycle. The PKA C‐subunits are regulated by dimeric regulatory (R) subunits, which form an inactive tetrameric complex in the absence of cAMP. Catalytic activity is unleashed by cAMP binding with high affinity to the R‐subunits. Structures of R‐subunit monomers bound to the C‐subunit demonstrated that the R‐subunit undergoes major conformational changes as it releases cAMP and binds to the C‐subunit. The cooperative binding of cAMP then releases the C‐subunit. Specificity in PKA signaling is achieved in part by the isoform diversity of the regulatory subunits and by targeting of the holoenzymes to specific sites by A Kinase Anchoring Proteins (AKAPs). The AKAP docking site is localized to the N‐terminal dimerization/docking (D/D) domain of the R‐subunits, a four helix bundle that binds with high affinity to an amphipathic helix in the AKAP. Structures of the D/D domains from RIIα and RIα bound to the same AKAP peptide from D‐AKAP2 reveal an isoform‐specific code for binding to AKAPs. Crystallization of tetrameric holoenzymes, coupled with small angle Xray an neutron scattering, demonstrates how full length holoenzymes are assembled and anchored to AKAPs and reveals for the first time the full allosteric potential of PKA signaling. Support for this work was provided by NIH DK54441, GM19301, and GM34921.