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Article Dans Une Revue Nature Communications Année : 2023

Membranes prime the RapGEF EPAC1 to transduce cAMP signaling

Marie Ley
Yves Ambroise
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  • IdHAL : yambroise

Résumé

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.

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Dates et versions

hal-04234947 , version 1 (10-10-2023)

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Candice Sartre, François Peurois, Marie Ley, Marie-Hélène Kryszke, Wenhua Zhang, et al.. Membranes prime the RapGEF EPAC1 to transduce cAMP signaling. Nature Communications, 2023, 14 (1), pp.4157. ⟨10.1038/s41467-023-39894-4⟩. ⟨hal-04234947⟩
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