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Structure and regulation of the cAMP-binding domains of Epac2

MPG-Autoren

Rehmann,  Holger
Max Planck Institute of Molecular Physiology, Max Planck Society;

Prakash,  Balaji
Max Planck Institute of Molecular Physiology, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons98740

Wolf,  Eva
Sonstige Wissenschaftliche Organisationseinheiten, Max Planck Institute of Molecular Physiology, Max Planck Society;

Rueppel,  Alma
Max Planck Institute of Molecular Physiology, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons98738

Wittinghofer,  Alfred
Sonstige Wissenschaftliche Organisationseinheiten, Max Planck Institute of Molecular Physiology, Max Planck Society;

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Zitation

Rehmann, H., Prakash, B., Wolf, E., Rueppel, A., De Rooij, J., Bos, J. L., et al. (2003). Structure and regulation of the cAMP-binding domains of Epac2. Nature Structural Biology, 10(1): 1, pp. 26-32. Retrieved from http://dx.doi.org/10.1038/nsb878.


Zitierlink: http://hdl.handle.net/11858/00-001M-0000-0014-0CBA-B
Zusammenfassung
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.