Membranes prime the RapGEF EPAC1 to transduce cAMP signaling.
Fiche publication
Date publication
juillet 2023
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Dr CIANFERANI Sarah
Tous les auteurs :
Sartre C, Peurois F, Ley M, Kryszke MH, Zhang W, Courilleau D, Fischmeister R, Ambroise Y, Zeghouf M, Cianferani S, Ferrandez Y, Cherfils J
Lien Pubmed
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.
Mots clés
Humans, Cytosol, Drug Discovery, Heart Diseases, Membranes, Transducers
Référence
Nat Commun. 2023 07 12;14(1):4157