Disordered Motifs and Domains in Cell Control
Tuesday Speaker Abstracts
PKA Signaling: Linkers, Loops, and Intrinsically Disorder Regions Control Allostery
Susan S. Taylor.
Departments of Pharmacology and Chemistry & Biochemistry, University of California, San
Diego, La Jolla, CA
The PKA catalytic subunit was the first protein kinase to be crystallized and gave us our first
glimpse of the fold that describes all protein kinases, which represent one of the largest gene
families. The two lobes that comprise the core are flanked by N-terminal and C-terminal tails
which wrap around both lobes. By capturing all the stages of catalysis in crystal structures we
appreciate the dynamic nature of these tails, how they wrap around the N-lobe and how they
undergo order-disorder transitions as part of the catalytic cycle. Ordering the activation loop by
the addition of a critical phosphate is another fundamental order/disorder transition that is a
conserved feature of most protein kinases. These dynamic features allow the kinases to function
as highly regulated molecular switches. In the case of PKA, the assembled C-subunit is packaged
with regulatory subunit dimers that contain the cAMP binding domains. The cyclic nucleotide
binding domains are highly dynamic allosteric signaling modules that have been conserved at all
stages of biology, and once again the fundamental features of this domain have been elucidated
by crystal structures of the isolated subunits. However, it is not until one sees full-length R
2
C
2
tetramers of the different PKA isoforms that one appreciates the importance of allostery for PKA
signaling. The order/disorder transitions of the linker regions of the R-subunit are an essential
feature of this regulation that is so critical for every mammalian cell.
(Funded in part by NIH grants GM34921, GM19301, and DK54441.)
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