Signaling through cAMP and cAMP-dependent protein kinase: diverse strategies for drug design.
The catalytic subunit of cAMP-dependent protein kinase has served as a prototype for the protein kinase superfamily for many years while structures of the cAMP-bound regulatory subunits have defined the conserved cyclic nucleotide binding (CNB) motif. It is only structures of the holoenzymes, however, that enable us to appreciate the molecular features of inhibition by the regulatory subunits as well as activation by cAMP. These structures reveal for the first time the remarkable malleability of the regulatory subunits and the CNB domains. At the same time, they allow us to appreciate that the catalytic subunit is not only a catalyst but also a scaffold that mediates a wide variety of protein:protein interactions. The holoenzyme structures also provide a new paradigm for designing isoform-specific activators and inhibitors of PKA. In addition to binding to the catalytic subunits, the regulatory subunits also use their N-terminal dimerization/docking domain to bind with high affinity to A Kinase Anchoring Proteins using an amphipathic helical motif. This targeting mechanism, which localizes PKA near to its protein substrates, is also a target for therapeutic intervention of PKA signaling.
Taylor
Susan S
SS
Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA 92093-0654, USA. staylor@ucsd.edu
Kim
Choel
C
Cheng
Cecilia Y
CY
Brown
Simon H J
SH
Wu
Jian
J
Kannan
Natarajan
N
D000818:Animals; D020134:Catalytic Domain / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D020035:Holoenzymes / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000378:metabolism; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction
D020035:Holoenzymes; D047908:Intracellular Signaling Peptides and Proteins; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D021122:Protein Subunits; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases