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

Author

Listed:
  • Holger Rehmann

    (University Medical Center Utrecht)

  • Joost Das

    (University Medical Center Utrecht)

  • Puck Knipscheer

    (The Netherlands Cancer Institute)

  • Alfred Wittinghofer

    (Max-Planck-Institut für Molekulare Physiologie)

  • Johannes L. Bos

    (University Medical Center Utrecht)

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 AMP1,2 and function in the control of diverse cellular processes, including cell adhesion and insulin secretion3. 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 β-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.

Suggested Citation

  • Holger Rehmann & Joost Das & Puck Knipscheer & Alfred Wittinghofer & Johannes L. Bos, 2006. "Structure of the cyclic-AMP-responsive exchange factor Epac2 in its auto-inhibited state," Nature, Nature, vol. 439(7076), pages 625-628, February.
    • Handle: RePEc:nat:nature:v:439:y:2006:i:7076:d:10.1038_nature04468
    DOI: 10.1038/nature04468
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    Cited by:

    1. Liliana Felicia Iannucci & Anna Maria D’Erchia & Ernesto Picardi & Daniela Bettio & Filippo Conca & Nicoletta Concetta Surdo & Giulietta Benedetto & Deborah Musso & Cristina Arrigoni & Marco Lolicato , 2023. "Cyclic AMP induces reversible EPAC1 condensates that regulate histone transcription," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Candice Sartre & François Peurois & Marie Ley & Marie-Hélène Kryszke & Wenhua Zhang & Delphine Courilleau & Rodolphe Fischmeister & Yves Ambroise & Mahel Zeghouf & Sarah Cianferani & Yann Ferrandez & , 2023. "Membranes prime the RapGEF EPAC1 to transduce cAMP signaling," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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