Transforming PKA into PKG - a structure-function approach to understand cyclic nucleotide selectivity
(2013)DOI: 10.1186/2050-6511-14-S1-P41
Description
cAMP-dependent protein kinase (PKA) and cGMP-dependent protein kinase (PKG) are the main effectors of distinct cyclic nucleotide pathways and are preferentially activated by cAMP or cGMP, respectively.
We recently characterized the isolated C-terminal cyclic nucleotide binding domain (CNB-B) of the human PKG Iβ as highly cGMP-selective (manuscript in preparation). In a crystal structure of the CNB-B two novel cGMP-specific interaction sites were identified in addition to the previously described threonine residue (T317) in the phosphate binding cassette [1]. Mutation of each individual site resulted in reduced cGMP-selectivity and interfered with cGMP-dependent activation of PKG Iβ.
To gain further insight into the molecular basis of cyclic nucleotide selectivity, we inserted two cGMP-specific interaction sites into the CNB-B of human PKA RIα by mutating corresponding residues. We hypothesize that this way cGMP-specific interaction contacts can be created in PKA and thereby modulate cAMP-selectivity [1,2].