Researchers at the University of Texas Medical Branch at Galveston and the University of California-San Diego School of Medicine have published a study that offers a new understanding of a protein critical to physiological processes involved in major diseases such as diabetes and cancer. This work could help scientists design drugs to battle these disorders.
The article was deemed a "Paper of the Week" by and will be on the cover of the Journal of Biological Chemistry. It is scheduled for publication May 20 and now available online.
"This study applied a powerful protein structural analysis approach to investigate how a chemical signal called cAMP turns on one of its protein switches, Epac2," said principal investigator Xiaodong Cheng, professor in the Department of Pharmacology and Toxicology and member of the Sealy Center for Structural Biology and Molecular Biophysics at UTMB.
The cAMP molecule controls many physiological processes, ranging from learning and memory in the brain and contractility and relaxation in the heart to insulin secretion in the pancreas. cAMP exerts its action in cells by binding to and switching on specific receptor proteins, which, when activated by cAMP, turn on additional signaling pathways.
Errors in cell signaling are responsible for diseases such as diabetes, cancer and heart failure. Understanding cAMP-mediated cell signaling, in which Epac2 is a major player, likely will facilitate the development of new therapeutic strategies specifically targeting the cAMP-Epac2 signaling components, according to the researchers.
The project involved an ongoing collaboration between Cheng's research group at UTMB, experts in the study of cAMP signaling, and UCSD professor of medicine Virgil Woods Jr. and colleagues at UCSD, pioneers in the development and application of hydrogen/deuterium exchange mass spectrometry (DXMS) technology. Compared with other protein-analysis techniques, DXMS is especially good at studying the structural motion of proteins.
Using this novel approach, the investigators were able to reveal, in fine detail, that cAMP interacts with its two known binding sites on Epac2 in a sequential fashion and that binding of cAMP changes the shape of the protein in a very specific way – switching on its activity by exposing further signaling interaction sites on Epac2.
"DXMS analysis has proved to be an amazingly powerful approach, alone or in combination with other techniques, in figuring out how proteins work as molecular machines, changing their shapes – or morphing – in the normal course of their function," said Woods. "This will be of great use in the identification and development of therapeutic drugs that target these protein motions."
Collaborators include Tamara Tsalkova and Fang Mei of the UTMB Department of Pharmacology and Toxicology; Mark A. White, associate professor in the UTMB Department of Biochemistry and Molecular Biology; and Dr. Sheng Li, Dr. Tong Liu and Daphne Wang of the UCSD Department of Medicine and Biomedical Sciences Graduate Program.
The study was funded by the National Institutes of Health and the John Sealy Memorial Endowment Fund for Biomedical Research. Based on its success at applying DXMS to the analysis of a number of important proteins, exemplified by this study with UTMB researchers, UCSD recently was awarded a generous NIH grant to implement "next-generation" advanced DXMS analysis for the benefit of scientists throughout the United States.
Photographs: http://bit.ly/kxhNeJ, http://bit.ly/jCzZSr, http://bit.ly/lEEU5d
Molly Dannenmaier | EurekAlert!
How brains surrender to sleep
23.06.2017 | IMP - Forschungsinstitut für Molekulare Pathologie GmbH
A new technique isolates neuronal activity during memory consolidation
22.06.2017 | Spanish National Research Council (CSIC)
An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.
Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...
Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.
Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...
Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.
As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...
Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.
With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...
Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine
Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...
19.06.2017 | Event News
13.06.2017 | Event News
13.06.2017 | Event News
23.06.2017 | Physics and Astronomy
23.06.2017 | Physics and Astronomy
23.06.2017 | Information Technology