ArticlePloS one2012
The auto-inhibitory role of the EPAC hinge helix as mapped by NMR.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed.
- A cryptic symmetry switch allosterically controls how the PF4 self-protein turns into a pathogenic antigen.Nature communications · 2026Article
- Aortic disease-linked mutations reveal unexpected convergent allosteric mechanisms of protein kinase G misregulation.Science advances · 2026Article
- Allosteric Protein Chemical Shift Perturbations are Ubiquitous.bioRxiv : the preprint server for biology · 2026Article
- NMR Studies of the Interactions between Sialyllactoses and the Polysialytransferase Domain for Polysialylation Inhibition.Current issues in molecular biology · 2024Article
- An NMR portrait of functional and dysfunctional allosteric cooperativity in cAMP-dependent protein kinase A.FEBS letters · 2023Review
- Analysis of coordinated NMR chemical shifts to map allosteric regulatory networks in proteins.Methods (San Diego, Calif.) · 2023Article
- QSAR models reveal new EPAC-selective allosteric modulators.RSC chemical biology · 2022Article
- Identification of core allosteric sites through temperature- and nucleus-invariant chemical shift covariance.Biophysical journal · 2022Article
- CHESPA/CHESCA-SPARKY: automated NMR data analysis plugins for SPARKY to map protein allostery.Bioinformatics (Oxford, England) · 2021Article
- Biochemical and structural characterization of analogs of MRE11 breast cancer-associated mutant F237C.Scientific reports · 2021Article
- Modulating Enzyme FunctionFrontiers in molecular biosciences · 2021Article
- Modeling Epac1 interactions with the allosteric inhibitor AM-001 by co-solvent molecular dynamics.Journal of computer-aided molecular design · 2020Article
- Allosteric Mechanisms of Nonadditive Substituent Contributions to Protein-Ligand Binding.Biophysical journal · 2020Article
- Mechanism of allosteric inhibition in theThe Journal of biological chemistry · 2020Article
- Review
- Novel Fluorescent Cyclic Nucleotide Derivatives to Study CNG and HCN Channel Function.Biophysical journal · 2019Article
- Mechanisms of Specific versus Nonspecific Interactions of Aggregation-Prone Inhibitors and Attenuators.Journal of medicinal chemistry · 2019Article
- Hydrophobic alkyl chains substituted to the 8-position of cyclic nucleotides enhance activation of CNG and HCN channels by an intricate enthalpy - entropy compensation.Scientific reports · 2018Article
- Insights into exchange factor directly activated by cAMP (EPAC) as potential target for cancer treatment.Molecular and cellular biochemistry · 2018Review
- Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development.Physiological reviews · 2018Review
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4 authors.
Funding
Abstract
The cyclic-AMP binding domain (CBD) is the central regulatory unit of exchange proteins activated by cAMP (EPAC). The CBD maintains EPAC in a state of auto-inhibition in the absence of the allosteric effector, cAMP. When cAMP binds to the CBD such auto-inhibition is released, leading to EPAC activation. It has been shown that a key feature of such cAMP-dependent activation process is the partial destabilization of a structurally conserved hinge helix at the C-terminus of the CBD. However, the role of this helix in auto-inhibition is currently not fully understood. Here we utilize a series of progressive deletion mutants that mimic the hinge helix destabilization caused by cAMP to show that such helix is also a pivotal auto-inhibitory element of apo-EPAC. The effect of the deletion mutations on the auto-inhibitory apo/inactive vs. apo/active equilibrium was evaluated using recently developed NMR chemical shift projection and covariance analysis methods. Our results show that, even in the absence of cAMP, the C-terminal region of the hinge helix is tightly coupled to other conserved allosteric structural elements of the CBD and perturbations that destabilize the hinge helix shift the auto-inhibitory equilibrium toward the apo/active conformations. These findings explain the apparently counterintuitive observation that cAMP binds more tightly to shorter than longer EPAC constructs. These results are relevant for CBDs in general and rationalize why substrates sensitize CBD-containing systems to cAMP. Furthermore, the NMR analyses presented here are expected to be generally useful to quantitatively evaluate how mutations affect conformational equilibria.
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