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Dynamics of Signaling by PKA
Author(s) -
Taylor S. S.
Publication year - 2007
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.21.5.a204-d
Subject(s) - protein subunit , allosteric regulation , gi alpha subunit , transferase , protein kinase a , gene isoform , chemistry , biology , biochemistry , biophysics , stereochemistry , kinase , microbiology and biotechnology , enzyme , gene
Cyclic AMP is an ancient signaling molecule and the C yclic N ucleotide B inding (CNB) domain to which it binds has been conserved from bacteria to man. In cAMP‐dependent protein kinase (PKA) two major signaling mechanisms have merged where cAMP binds to the regulatory (R) subunit and unleashes the phosphoryl transferase activity of the catalytic (C) subunit. While we have understood the molecular features of the C‐subunit and the cAMP‐bound R‐subunits for some time, only recently have the molecular features of the holoenzyme complexes been revealed with the crystal structures of the RIα and RIIα subunits bound to C. These structures show the remarkable malleability of the two tandem CNBs in each R subunit as they release cAMP and wrap around the large lobe of the C‐subunit. The structures demonstrate the extended allosteric networks that reach across both subunits and also define the C‐subunit as a scaffold protein in addition to its role as a catalyst. The αG‐helix and the Activation Loop in the C‐subunit define the boundaries of the extended surface (4000Å 2 ) where both R‐subunits dock. The structures also demonstrate significant isoform differences. The type I R‐subunit with its pseudosubstrate inhibitor site locks the complex into a fully closed conformational state where ATP and two magnesium ions are essential. In contrast, the RII‐subunit is a substrate as well as an inhibitor. It also docks onto the large lobe but in an ATP independent manner with the small lobe of the C‐subunit in an open conformation. The interactions of the RI and RII‐subunits with the C‐subunit in cells in the presence of cAMP also show isoform differences that likely contribute to specificity. Isoform differences also distinguish the interactions of the RI and RII subunits with A Kinase Anchoring Proteins (AKAPs), and these interactions introduce yet another level of dynamics into PKA signaling. With well‐defined structures of inhibited and dissociated states as well as anchored states, PKA provides an excellent prototype for understanding the multiscale dynamics associated with cell signaling events. (Funding for this work has come from the National Institutes of Health (GM34921, GM19301, and DK54441) and from the Howard Hughes Medical Institute.)