Dynamics of crucial protein 'switch' revealedMay 18, 2011
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.
University of Texas Medical Branch at Galveston
Related Chemical Signal Current Events and Chemical Signal News Articles
An enzyme and synaptic plasticity
A small, "empty" space teeming with activity: a synapse is a complex structure where the neural (electrical) signal from the presynaptic neuron, as it travels towards its target -a muscle, a gland or another neuron - turns into a chemical signal capable of crossing the synaptic space before becoming electrical again once on the other side.
Blame it on the astrocytes
In the brains of all vertebrates, information is transmitted through synapses, a mechanism that allows an electric or chemical signal to be passed from one brain cell to another.
Domestication syndrome: White patches, baby faces and tameness
More than 140 years ago, Charles Darwin noticed something peculiar about domesticated mammals.
Promising approach to slow brain degeneration in a model of Huntington's disease uncovered
Research presented by Dr. Lynn Raymond, from the University of British Columbia, shows that blocking a specific class of glutamate receptors, called extrasynaptic NMDA receptors, can improve motor learning and coordination, and prevent cell death in animal models of Huntington disease.
Signals found that recruit host animals' cells, enabling breast cancer metastasis
Working with mice, Johns Hopkins researchers report they have identified chemical signals that certain breast cancers use to recruit two types of normal cells needed for the cancers' spread.
Plankton make scents for seabirds and a cooler planet
The top predators of the Southern Ocean, far-ranging seabirds, are tied both to the health of the ocean ecosystem and to global climate regulation through a mutual relationship with phytoplankton, according to newly published work from the University of California, Davis.
The 'entrance exam' that is key to a successful pregnancy
Researchers have discovered how an 'entrance exam' set by the womb determines if the implantation of an embryo is successful; potentially a milestone for advances in pregnancy treatments.
York U molecular communication researchers send world's first text message using vodka
After successfully text messaging 'O Canada' using evaporated vodka, two York University researchers and their UK-based counterpart say their simple system can be used where conventional wireless technology fails.
University of East Anglia research shows how females choose the 'right' sperm
Researchers investigated salmon and trout, which fertilize externally in river water. The two species occasionally hybridize in the wild, but since hybrid offspring become reproductive dead-ends, females of both species are under selection to avoid hybrid fertilizations, and instead promote external fertilization by their own species' sperm.
Haste and waste on neuronal pathways
Researchers of the Department of Biosystems Science and Engineering of ETH Zurich were able to measure the speed of neuronal signal conduction along segments of single axons in neuronal cultures by using a high-resolution electrical method.
More Chemical Signal Current Events and Chemical Signal News Articles