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Publication : Structure of the cyclic-AMP-responsive exchange factor Epac2 in its auto-inhibited state.

First Author  Rehmann H Year  2006
Journal  Nature Volume  439
Issue  7076 Pages  625-8
PubMed ID  16452984 Mgi Jnum  J:245330
Mgi Id  MGI:5917821 Doi  10.1038/nature04468
Citation  Rehmann H, et al. (2006) Structure of the cyclic-AMP-responsive exchange factor Epac2 in its auto-inhibited state. Nature 439(7076):625-8
abstractText  Epac proteins (exchange proteins directly activated by cAMP) are guanine-nucleotide-exchange factors (GEFs) for the small GTP-binding proteins Rap1 and Rap2 that are directly regulated by the second messenger cyclic AMP and function in the control of diverse cellular processes, including cell adhesion and insulin secretion. Here we report the three-dimensional structure of full-length Epac2, a 110-kDa protein that contains an amino-terminal regulatory region with two cyclic-nucleotide-binding domains and a carboxy-terminal catalytic region. The structure was solved in the absence of cAMP and shows the auto-inhibited state of Epac. The regulatory region is positioned with respect to the catalytic region by a rigid, tripartite beta-sheet-like structure we refer to as the 'switchboard' and an ionic interaction we call the 'ionic latch'. As a consequence of this arrangement, the access of Rap to the catalytic site is sterically blocked. Mutational analysis suggests a model for cAMP-induced Epac activation with rigid body movement of the regulatory region, the features of which are universally conserved in cAMP-regulated proteins.
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