The two GAF domains in phosphodiesterase 2A have distinct roles in dimerization and in cGMP binding
Copyright policy )The two GAF domains in phosphodiesterase 2A have distinct roles in dimerization and in cGMP binding
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-Å 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.
- KU Leuven Belgium
- University of Washington United States
- University of Mary United States
- Howard Hughes Medical Institute United States
Models, Molecular, Dose-Response Relationship, Drug, Sequence Homology, Amino Acid, Protein Conformation, Amino Acid Motifs, Molecular Sequence Data, Crystallography, X-Ray, Cyclic Nucleotide Phosphodiesterases, Type 2, Models, Biological, Protein Structure, Tertiary, Mice, 3',5'-Cyclic-AMP Phosphodiesterases, Cyclic AMP, Animals, Amino Acid Sequence, Protein Structure, Quaternary, Cyclic GMP, Dimerization, Protein Binding
Models, Molecular, Dose-Response Relationship, Drug, Sequence Homology, Amino Acid, Protein Conformation, Amino Acid Motifs, Molecular Sequence Data, Crystallography, X-Ray, Cyclic Nucleotide Phosphodiesterases, Type 2, Models, Biological, Protein Structure, Tertiary, Mice, 3',5'-Cyclic-AMP Phosphodiesterases, Cyclic AMP, Animals, Amino Acid Sequence, Protein Structure, Quaternary, Cyclic GMP, Dimerization, Protein Binding
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