ArticleThe Journal of biological chemistry2011
Mechanism of intracellular cAMP sensor Epac2 activation: cAMP-induced conformational changes identified by amide hydrogen/deuterium exchange mass spectrometry (DXMS).
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
52 citing papers in PubMed, 72 citations in OpenAlex.
- H7N9 influenza virus neutralizing antibodies that possess few somatic mutations.The Journal of clinical investigation · 2016Trial
- Role of exchange proteins directly activated by cAMP signaling in vascular remodeling.Pharmacological reviews · 2025Review
- Pan-H7 influenza human antibody virus neutralization depends on avidity and steric hindrance.JCI insight · 2025Article
- A SUMO-interacting motif in the guanine nucleotide exchange factor EPAC1 is required for subcellular targeting and function.bioRxiv : the preprint server for biology · 2025Article
- Protein SUMOylation promotes cAMP-independent EPAC1 activation.Cellular and molecular life sciences : CMLS · 2024Article
- Membranes prime the RapGEF EPAC1 to transduce cAMP signaling.Nature communications · 2023Article
- Identification of core allosteric sites through temperature- and nucleus-invariant chemical shift covariance.Biophysical journal · 2022Article
- Identification of oleoylethanolamide as an endogenous ligand for HIF-3α.Nature communications · 2022Article
- Structural basis for the mechanisms of human presequence protease conformational switch and substrate recognition.Nature communications · 2022Article
- Human antibody recognition of H7N9 influenza virus HA following natural infection.JCI insight · 2021Article
- Physiological effects of nutrients on insulin release by pancreatic beta cells.Molecular and cellular biochemistry · 2021Review
- Article
- Influenza H7N9 Virus Neuraminidase-Specific Human Monoclonal Antibodies Inhibit Viral Egress and Protect from Lethal Influenza Infection in Mice.Cell host & microbe · 2019Article
- Review
- CMT disease severity correlates with mutation-induced open conformation of histidyl-tRNA synthetase, not aminoacylation loss, in patient cells.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- A Site of Vulnerability on the Influenza Virus Hemagglutinin Head Domain Trimer Interface.Cell · 2019Article
- Bidirectional modulation of HIF-2 activity through chemical ligands.Nature chemical biology · 2019Article
- Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development.Physiological reviews · 2018Review
- Article
- From Ras to Rap and Back, a Journey of 35 Years.Cold Spring Harbor perspectives in medicine · 2018Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Epac2, a guanine nucleotide exchange factor, regulates a wide variety of intracellular processes in response to second messenger cAMP. In this study, we have used peptide amide hydrogen/deuterium exchange mass spectrometry to probe the solution structural and conformational dynamics of full-length Epac2 in the presence and absence of cAMP. The results support a mechanism in which cAMP-induced Epac2 activation is mediated by a major hinge motion centered on the C terminus of the second cAMP binding domain. This conformational change realigns the regulatory components of Epac2 away from the catalytic core, making the later available for effector binding. Furthermore, the interface between the first and second cAMP binding domains is highly dynamic, providing an explanation of how cAMP gains access to the ligand binding sites that, in the crystal structure, are seen to be mutually occluded by the other cAMP binding domain. Moreover, cAMP also induces conformational changes at the ionic latch/hairpin structure, which is directly involved in RAP1 binding. These results suggest that in addition to relieving the steric hindrance imposed upon the catalytic lobe by the regulatory lobe, cAMP may also be an allosteric modulator directly affecting the interaction between Epac2 and RAP1. Finally, cAMP binding also induces significant conformational changes in the dishevelled/Egl/pleckstrin (DEP) domain, a conserved structural motif that, although missing from the active Epac2 crystal structure, is important for Epac subcellular targeting and in vivo functions.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.