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A simple electrostatic switch important in the activation of type I protein kinase A by cyclic AMP
Author(s) -
Vigil Dominico,
Lin JungHsin,
Sotriffer Christoph A.,
Pennypacker Juniper K.,
McCammon J. Andrew,
Taylor Susan S.
Publication year - 2006
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1110/ps.051723606
Subject(s) - protein subunit , protein kinase a , salt bridge , biophysics , helix (gastropod) , gi alpha subunit , binding site , biochemistry , microbiology and biotechnology , chemistry , kinase , biology , mutant , gene , ecology , snail
Cyclic AMP activates protein kinase A by binding to an inhibitory regulatory (R) subunit and releasing inhibition of the catalytic (C) subunit. Even though crystal structures of regulatory and catalytic subunits have been solved, the precise molecular mechanism by which cyclic AMP activates the kinase remains unknown. The dynamic properties of the cAMP binding domain in the absence of cAMP or C‐subunit are also unknown. Here we report molecular‐dynamics simulations and mutational studies of the RIα R‐subunit that identify the C‐helix as a highly dynamic switch which relays cAMP binding to the helical C‐subunit binding regions. Furthermore, we identify an important salt bridge which links cAMP binding directly to the C‐helix that is necessary for normal activation. Additional mutations show that a hydrophobic “hinge” region is not as critical for the cross‐talk in PKA as it is in the homologous EPAC protein, illustrating how cAMP can control diverse functions using the evolutionarily conserved cAMP‐binding domains.