Proceedings of the National Academy of Sciences · 2002 · 286 citations · 34 references
Life SciencesBiochemistryMolecular BiologyCell SignalingSignal TransductionStructural BiologyCyclic Nucleotide SignalingLigand BindingProtein DomainsProtein StructureStructural GenomicsStructural MotifsAdenylate Cyclase SignalingAdenylyl Cyclase RegulationAdenylyl Cyclase SignalingCatalytic ActivityCyclic Nucleotide PhosphodiesterasesNucleotide Binding DomainsNucleotide-binding MotifProtein Dimerization Domains
Cyclic nucleotide phosphodiesterases (PDEs) regulate all pathways that use cGMP or cAMP as a second messenger. Five of the 11 PDE families have regulatory segments containing GAF domains, 3 of which are known to bind cGMP. In PDE2 binding of cGMP to the GAF domain causes an activation of the catalytic activity by a mechanism that apparently is shared even in the adenylyl cyclase of Anabaena, an organism separated from mouse by 2 billion years of evolution. The 2.9-A crystal structure of the mouse PDE2A regulatory segment reported in this paper reveals that the GAF A domain functions as a dimerization locus. The GAF B domain shows a deeply buried cGMP displaying a new cGMP-binding motif and is the first atomic structure of a physiological cGMP receptor with bound cGMP. Moreover, this cGMP site is located well away from the region predicted by previous mutagenesis and structural genomic approaches.
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