title: Cyclic nucleotide binding GAF domains from phosphodiesterases: structural and mechanistic insights.
abstract: GAF domains regulate the catalytic activity of certain vertebrate cyclic nucleotide phosphodiesterases (PDEs) by allosteric, noncatalytic binding of cyclic nucleotides. GAF domains arranged in tandem are found in PDE2, -5, -6, -10, and -11, all of which regulate the cellular concentrations of the second messengers cAMP and/or cGMP. Nucleotide binding to GAF domains affects the overall conformation and the catalytic activity of full-length PDEs. The cyclic nucleotide-bound GAF domains from PDE2, -5, -6, and -10 all adopt a conserved fold but show subtle differences within the binding pocket architecture that account for a large range of nucleotide affinities and selectivity. NMR data and details from the structure of full-length nucleotide-free PDE2A reveal the dynamic nature and magnitude of the conformational change that accompanies nucleotide binding. The discussed GAF domain structures further reveal differences in dimerization properties and highlight the structural diversity within GAF domain-containing PDEs.
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Clemens C
authors.initials: CC
authors.lastname: Heikaus
authors.affiliation: Pfizer, Inc., PGRD, Groton, 558 Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Jayvardhan
authors.initials: J
authors.lastname: Pandit
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Electronic address: klevit@u.washington.edu.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Klevit
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D000242:Cyclic AMP / Q000737:chemistry / Q000378:metabolism*; D006152:Cyclic GMP / Q000737:chemistry / Q000378:metabolism*; D019281:Dimerization; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
chemical_list: D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP