Membranes prime the RapGEF EPAC1 to transduce cAMP signaling

Candice Sartre, François Peurois, Marie Ley, Marie-Hélène Kryszke, Wenhua Zhang, Delphine Courilleau, Rodolphe Fischmeister, Yves Ambroise, Mahel Zeghouf, Sarah Cianferani, Yann Ferrandez and Jacqueline Cherfils ()
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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

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39894-4

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