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.
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
