Nature Structural Biology10, 26 - 32 (2002)
Published online: 9 December 2002; | doi:10.1038/nsb878
Structure and regulation of the cAMP-binding domains of Epac2
Holger Rehmann1, 2, 3, Balaji Prakash1, 2, 4, Eva Wolf1, 2, Alma Rueppel2, Johan de Rooij3, Johannes L. Bos3
& Alfred Wittinghofer2
1
These authors contributed equally to this work.
2
Max-Planck Institut für Molekulare Physiologie, Otto Hahn Strasse 11, D-44227, Dortmund, Germany.
3
Department of Physiological Chemistry and Center for Biomedical Genetics, University Medical Centre Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
4
Present address: Department of Biological Sciences and Bio-Engineering, Indian Institute of Technology, Kanpur 208 016, India.
Cyclic adenosine monophosphate (cAMP) is a universal second messenger that, in eukaryotes, was believed to act only on cAMP-dependent protein kinase A (PKA) and cyclic nucleotide-regulated ion channels. Recently, guanine nucleotide exchange factors specific for the small GTP-binding proteins Rap1 and Rap2 (Epacs) were described, which are also activated directly by cAMP. Here, we have determined the three-dimensional structure of the regulatory domain of Epac2, which consists of two cyclic nucleotide monophosphate (cNMP)-binding domains and one DEP (Dishevelled, Egl, Pleckstrin) domain. This is the first structure of a cNMP-binding domain in the absence of ligand, and comparison with previous structures, sequence alignment and biochemical experiments allow us to delineate a mechanism for cyclic nucleotide-mediated conformational change and activation that is most likely conserved for all cNMP-regulated proteins. We identify a hinge region that couples cAMP binding to a conformational change of the C-terminal regions. Mutations in the hinge of Epac can uncouple cAMP binding from its exchange activity.
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