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Crystal structure of a complex between the catalytic and regulatory (RI alpha 91‐379) subunits of PKA
Author(s) -
Kim Choel W,
Cheng Cecila,
NguyenHuu Xuong,
Taylor Susan S
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a492-a
Subject(s) - protein subunit , chemistry , crystal structure , binding site , stereochemistry , gi alpha subunit , crystallography , adenosine monophosphate , docking (animal) , adenosine , biochemistry , medicine , nursing , gene
In order to understand the activation mechanism of cyclic adenosine monophosphate (cAMP)–dependent protein kinase (PKA), we solved a high resolution crystal structure a complex between the catalytic (C) subunit and regulatory (RI alpha 91–379) subunit. RI alpha (91–379) contains both tandem cAMP binding domains, CBD‐A and CBD‐B. Our previous structure of a complex with RI alpha (91–244) containing only CBD‐A predicted major changes in the position of CBD‐B (Kim, et al. Science). The crystal structure of RI alpha (91–379) : C complex not only validates our previous complex but also reveals a new interface that had been predicted by hydrogen/deuterium exchange (Anand, et al., PNAS). As predicted, the docking of RI alpha (91–379) onto the C‐subunit involves drastic changes in the global orientation of the two CBDs relative to each other and in the subhelical domain of CBD‐B itself. In contrast to the contacts made by CBD‐A, the interface between CBD‐B and the large lobe of the C‐subunit is highly localized and solvated. The structure also reveals an electrostatic switch that couples the two CBDs and explains the ordered bindings of cAMP that is associated with activation of the holoenzyme. Specifically, binding of cAMP to CBD‐B precedes binding of CBD‐A and binding of cAMP to CBD‐A causes dissociation of the complex. (Funded in part by NIH grants GM34921)