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Membranes prime the RapGEF EPAC1 to transduce cAMP signaling

Author

Listed:
  • Candice Sartre

    (Ecole Normale Supérieure Paris-Saclay, CNRS)

  • François Peurois

    (Ecole Normale Supérieure Paris-Saclay, CNRS)

  • Marie Ley

    (IPHC, CNRS UMR 7178, Infrastructure Nationale de Protéomique ProFI – FR2048)

  • Marie-Hélène Kryszke

    (Ecole Normale Supérieure Paris-Saclay, CNRS)

  • Wenhua Zhang

    (Ecole Normale Supérieure Paris-Saclay, CNRS)

  • Delphine Courilleau

    (IPSIT-CIBLOT, Inserm US31, CNRS UAR3679)

  • Rodolphe Fischmeister

    (INSERM, UMR-S 1180)

  • Yves Ambroise

    (CEA, Service de Chimie Bioorganique et de Marquage)

  • Mahel Zeghouf

    (Ecole Normale Supérieure Paris-Saclay, CNRS)

  • Sarah Cianferani

    (IPHC, CNRS UMR 7178, Infrastructure Nationale de Protéomique ProFI – FR2048)

  • Yann Ferrandez

    (Ecole Normale Supérieure Paris-Saclay, CNRS)

  • Jacqueline Cherfils

    (Ecole Normale Supérieure Paris-Saclay, CNRS)

Abstract

EPAC1, a cAMP-activated GEF for Rap GTPases, is a major transducer of cAMP signaling and a therapeutic target in cardiac diseases. The recent discovery that cAMP is compartmentalized in membrane-proximal nanodomains challenged the current model of EPAC1 activation in the cytosol. Here, we discover that anionic membranes are a major component of EPAC1 activation. We find that anionic membranes activate EPAC1 independently of cAMP, increase its affinity for cAMP by two orders of magnitude, and synergize with cAMP to yield maximal GEF activity. In the cell cytosol, where cAMP concentration is low, EPAC1 must thus be primed by membranes to bind cAMP. Examination of the cell-active chemical CE3F4 in this framework further reveals that it targets only fully activated EPAC1. Together, our findings reformulate previous concepts of cAMP signaling through EPAC proteins, with important implications for drug discovery.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39894-4
    DOI: 10.1038/s41467-023-39894-4
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    References listed on IDEAS

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    1. Louis Renault & Bernard Guibert & Jacqueline Cherfils, 2003. "Structural snapshots of the mechanism and inhibition of a guanine nucleotide exchange factor," Nature, Nature, vol. 426(6966), pages 525-530, December.
    2. Holger Rehmann & Ernesto Arias-Palomo & Michael A. Hadders & Frank Schwede & Oscar Llorca & Johannes L. Bos, 2008. "Structure of Epac2 in complex with a cyclic AMP analogue and RAP1B," Nature, Nature, vol. 455(7209), pages 124-127, September.
    3. 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.
    4. Johan de Rooij & Fried J. T. Zwartkruis & Mark H. G. Verheijen & Robbert H. Cool & Sebastian M. B. Nijman & Alfred Wittinghofer & Johannes L. Bos, 1998. "Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP," Nature, Nature, vol. 396(6710), pages 474-477, December.
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