PKA Type II
Holoenzyme Reveals a Combinatorial Strategy for Isoform Diversity
Jian Wu,1
Simon H. J. Brown,1
Sventja von Daake,1
Susan S. Taylor1,2*
The catalytic (C) subunit of cyclic adenosine monophosphate (cAMP)–dependent protein kinase (PKA) is inhibited by two classes of regulatory subunits, RI and RII. The RII subunits are substrates as well as inhibitors and do not require adenosine triphosphate (ATP) to form holoenzyme, which distinguishes them from RI subunits. To understand the molecular basis for isoform diversity, we solved the crystal structure of an RII
holoenzyme and compared it to the RI holoenzyme. Unphosphorylated RII(90-400), a deletion mutant, undergoes major conformational changes as both of the cAMP-binding domains wrap around the C subunit's large lobe. The hallmark of this conformational reorganization is the helix switch in domain A. The C subunit is in an open conformation, and its carboxyl-terminal tail is disordered. This structure demonstrates the conserved and isoform-specific features of RI and RII and the importance of ATP, and also provides a new paradigm for designing isoform-specific activators or antagonists for PKA.
1 Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
2 Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
* To whom correspondence should be addressed. E-mail: staylor{at}ucsd.edu
