PXD040227

PXD040227 is an original dataset announced via ProteomeXchange.

Title	Membranes prime the RapGEF EPAC1 to transduce cAMP signaling
Description	EPAC1, a cAMP-activated GEF for Rap GTPases, is a major transducer of cAMP signaling in normal cells 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 in the absence of cAMP, that they increase its affinity for cAMP by 2 orders of magnitude, and that they synergize with cAMP to yield maximal GEF activity. Thus, EPAC1 has four states that differ in their affinity for cAMP and GEF efficiency. In cells, where cytosolic cAMP is low, this implies that EPAC1 must be primed by membranes to bind cAMP. Examination of the inhibitory mechanism of the cardiomyocyte-active chemical CE3F4 in this new framework further reveals that it targets only only membrane- and cAMP-activated EPAC1. Together, our findings reformulate previous concepts of cAMP signaling to include a hitherto overlooked role of membranes through EPAC proteins, with important implications for drug discovery.
HostingRepository	PRIDE
AnnounceDate	2023-04-07
AnnouncementXML	Submission_2023-04-07_05:25:18.203.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	MarieLEY
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Synapt MS

Revision	Datetime	Status	ChangeLog Entry
0	2023-02-17 02:29:20	ID requested
⏵ 1	2023-04-07 05:25:18	announced

Dataset with its publication pending

ProteomeXchange project tag: Hydrogen Deuterium Exchange (HDX-MS)

submitter keyword: HDXMS,EPAC1

CIANFERANISarah
contact affiliation	LSMBO IPHC CNRS Strasbourg France
contact email	sarah.cianferani@unistra.fr
lab head
MarieLEY
contact affiliation	CNRS, IPHC, LSMBO
contact email	marie.ley@etu.unistra.fr
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/04/PXD040227

PRIDE project URI

• PRIDE
  1. PXD040227
     1. Label: PRIDE project
     2. Name: Membranes prime the RapGEF EPAC1 to transduce cAMP signaling