2BYV

Structure of the cAMP responsive exchange factor Epac2 in its auto- inhibited state

Summary for 2BYV

• Entry DOI: 10.2210/pdb2byv/pdb
• Related: 1O7F
• Descriptor: RAP GUANINE NUCLEOTIDE EXCHANGE FACTOR 4 (2 entities in total)
• Functional Keywords: epac2, camp-gef2, camp, cyclic nucleotide, gef, exchange factor, regulation, auto-inhibition, cdc25 homology domain
• Biological source: MUS MUSCULUS (MOUSE)
• Cellular location: Cytoplasm: Q9EQZ6
• Total number of polymer chains: 1
• Total formula weight: 114150.55

Authors

Rehmann, H.,Wittinghofer, A.,Bos, J.L. (deposition date: 2005-08-08, release date: 2006-02-02, Last modification date: 2023-12-13)

Primary citation

Rehmann, H.,Das, J.,Knipscheer, P.,Wittinghofer, A.,Bos, J.L.
Structure of the Cyclic-AMP Responsive Exchange Factor Epac2 in its Auto-Inhibited State
Nature, 439:625-, 2006

PubMed Abstract: 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.

PubMed: 16452984
DOI: 10.1038/NATURE04468

Experimental method

X-RAY DIFFRACTION (2.7 Å)