Mechanism of cAMP Partial Agonism in Protein Kinase G (PKG).
J Biol Chem
; 290(48): 28631-41, 2015 Nov 27.
Article
in En
| MEDLINE
| ID: mdl-26370085
ABSTRACT
Protein kinase G (PKG) is a major receptor of cGMP and controls signaling pathways often distinct from those regulated by cAMP. Hence, the selective activation of PKG by cGMP versus cAMP is critical. However, the mechanism of cGMP-versus-cAMP selectivity is only limitedly understood. Although the C-terminal cyclic nucleotide-binding domain B of PKG binds cGMP with higher affinity than cAMP, the intracellular concentrations of cAMP are typically higher than those of cGMP, suggesting that the cGMP-versus-cAMP selectivity of PKG is not controlled uniquely through affinities. Here, we show that cAMP is a partial agonist for PKG, and we elucidate the mechanism for cAMP partial agonism through the comparative NMR analysis of the apo, cGMP-, and cAMP-bound forms of the PKG cyclic nucleotide-binding domain B. We show that although cGMP activation is adequately explained by a two-state conformational selection model, the partial agonism of cAMP arises from the sampling of a third, partially autoinhibited state.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Models, Molecular
/
Cyclic AMP
/
Cyclic GMP
/
Cyclic GMP-Dependent Protein Kinase Type I
Limits:
Humans
Language:
En
Journal:
J Biol Chem
Year:
2015
Type:
Article