6H7E

GEF regulatory domain

Summary for 6H7E

• Entry DOI: 10.2210/pdb6h7e/pdb
• Descriptor: cDNA FLJ56134, highly similar to Rap guanine nucleotide exchange factor 3, ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE, SULFATE ION, ... (4 entities in total)
• Functional Keywords: gef, camp, regulatory, membrane binding domain, epac, structural protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 61423.74

Authors

Ferrandez, Y.,Cherfils, J.,Peurois, F. (deposition date: 2018-07-31, release date: 2020-02-19, Last modification date: 2023-12-20)

Primary citation

Sartre, C.,Peurois, F.,Ley, M.,Kryszke, M.H.,Zhang, W.,Courilleau, D.,Fischmeister, R.,Ambroise, Y.,Zeghouf, M.,Cianferani, S.,Ferrandez, Y.,Cherfils, J.
Membranes prime the RapGEF EPAC1 to transduce cAMP signaling.
Nat Commun, 14:4157-4157, 2023

PubMed 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.

PubMed: 37438343
DOI: 10.1038/s41467-023-39894-4

Experimental method

X-RAY DIFFRACTION (2.3 Å)