Dynamics of signaling by PKA.
The catalytic and regulatory subunits of cAMP-dependent protein kinase (PKA) are highly dynamic signaling proteins. In its dissociated state the catalytic subunit opens and closes as it moves through its catalytic cycle. In this subunit, the core that is shared by all members of the protein kinase family is flanked by N- and C-terminal segments. Each are anchored firmly to the core by well-defined motifs and serve to stabilize the core. Protein kinases are not only catalysts, they are also scaffolds. One of their major functions is to bind to other proteins. In addition to its interactions with the N- and C- termini, the catalytic subunit interacts with its inhibitor proteins, PKI and the regulatory subunits. Both bind with subnanomolar affinity. To achieve this tight binding requires docking of a substrate mimetic to the active site cleft as well as a peripheral docking site. The peripheral site used by PKI is distinct from that used by RIalpha as revealed by a recent structure of a C:RIalpha complex. Upon binding to the catalytic subunit, the linker region of RIalpha becomes ordered. In addition, cAMP-binding domain A undergoes major conformational changes. RIalpha is a highly malleable protein. Using small angle X-ray scattering, the overall shape of the regulatory subunits and corresponding holoenzymes have been elucidated. These studies reveal striking and surprising isoform differences.
Taylor
Susan S
SS
Howard Hughes Medical Institute, Department of Chemistry and Biochemistry and Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0654, USA. staylor@ucsd.edu
Kim
Choel
C
Vigil
Dominico
D
Haste
Nina M
NM
Yang
Jie
J
Wu
Jian
J
Anand
Ganesh S
GS
D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry* / Q000378:metabolism*; D020035:Holoenzymes; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction
D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D020035:Holoenzymes; C517834:PRKAR1A protein, human; D020033:Protein Isoforms; D017868:Cyclic AMP-Dependent Protein Kinases