title: cAMP-dependent allostery and dynamics in Epac: an NMR view.
abstract: Epac (exchange protein directly activated by cAMP) is a critical cAMP receptor, which senses cAMP and couples the cAMP signal to the catalysis of guanine exchange in the Rap substrate. In the present paper, we review the NMR studies that we have undertaken on the CBD (cyclic-nucleotide-binding domain) of Epac1. Our NMR investigations have shown that cAMP controls distal autoinhibitory interactions through long-range modulations in dynamics. Such dynamically mediated allosteric effects contribute not only to the cAMP-dependent activation of Epac, but also to the selectivity of Epac for cAMP in contrast with cGMP. In addition, we have mapped the interaction networks that couple the cAMP-binding site to the sites involved in the autoinhibitory interactions, using a method based on the covariance analysis of NMR chemical shifts. We anticipate that this approach is generally applicable to dissect allosteric networks in signalling domains.
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada, L8S 4M1.
authors.forename: Rajeevan
authors.initials: R
authors.lastname: Selvaratnam
authors.forename: Madoka
authors.initials: M
authors.lastname: Akimoto
authors.forename: Bryan
authors.initials: B
authors.lastname: VanSchouwen
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Melacini
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D020816:Amino Acid Motifs; D000818:Animals; D000242:Cyclic AMP / Q000737:chemistry*; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D011485:Protein Binding
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C116122:RAPGEF3 protein, human; D000242:Cyclic AMP