Dynamics of crucial protein 'switch' revealed

May 18, 2011

Cell signaling networks tied to diabetes and cancer

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

Molecular switch for cheaper biofuel
Lignocellulosic waste such as sawdust or straw can be used to produce biofuel - but only if the long cellulose and xylan chains can be successfully broken down into smaller sugar molecules.

Clues to heart disease in unexpected places, Temple researchers discover
A major factor in the advance of heart disease is the death of heart tissue, a process that a team of scientists at Temple University School of Medicine's (TUSM) Center for Translational Medicine think could be prevented with new medicines.

Surf's up: Turbulence tells sea urchins to settle down
Tumbling in the waves as they hit a rocky shore tells purple sea urchin larvae it's time to settle down and look for a spot to grow into an adult, researchers at the University of California, Davis, Bodega Marine Laboratory have found.

New findings into conquering influenza
Reseachers from the University of Melbourne and The Walter and Eliza Hall Institute (WEHI) have discovered a new protein that protects against viral infections such as influenza.

Crayfish species proves to be the ultimate survivor
One of the most invasive species on the planet is able to source food from the land as well as its usual food sources in the water, research from Queen Mary, University of London has found.

Plant perfumes woo beneficial bugs
Scientists funded by the Biotechnology and Biological Sciences Research Council (BBSRC) have discovered that maize crops emit chemical signals which attract growth-promoting microbes to live amongst their roots.

Orientation of desert ants: Every cue counts
Desert ants have adapted to a life in a barren environment which only provides very few landmarks for orientation.

From 'Refrigerator Mothers' to untangling the genetic roots of autism
With the "Refrigerator Mother" notion about the cause of autism a distant and discredited memory, scientists are making remarkable progress in untangling the genetic roots of the condition, which affects millions of children and adults, according to an article in the current edition of Chemical & Engineering News.

Carp dominate crayfish in invasive species battleground
Louisiana red swamp crayfish and common carp are two of the most invasive species on the planet yet how they interact has only recently been revealed by scientists at Queen Mary, University of London.

Manipulating way bacteria 'talk' could have practical applications, Texas A&M profs say
By manipulating the way bacteria "talk" to each other, researchers at Texas A&M University have achieved an unprecedented degree of control over the formation and dispersal of biofilms - a finding with potentially significant health and industrial applications, particularly to bioreactor technology.

More Chemical Signal Current Events and Chemical Signal News Articles

Chemical Signals in Vertebrates 12
by Marion L East (Editor), Martin Dehnhard (Editor)

Three invited international experts present overviews of recent developments in key fields and will submit chapters for the book. Jane Hurst from Liverpool University in the UK presents an overview on the function, mechanisms and evolution of chemical signals, Penelope Hawkins from the University of Western Australia will detail the importance of male odors in female mate-choice and the priming of female reproduction, and Francesco Bonadonna from CNRS-CEFE, Montpellier in France presents an overview of the importance of chemical signals for the formation and maintenance of pair-bonds, parent – offspring recognition and navigation in seabirds. Select submissions are invited by the scientific committee to contribute chapters.

Cooked: A Natural History of Transformation
by Michael Pollan (Author)

In Cooked, Michael Pollan explores the previously uncharted territory of his own kitchen. Here, he discovers the enduring power of the four classical elementsfire, water, air, and earthto transform the stuff of nature into delicious things to eat and drink. Apprenticing himself to a succession of culinary masters, Pollan learns how to grill with fire, cook with liquid, bake bread, and ferment everything from cheese to beer.

Each section of Cooked tracks Pollan’s effort to master a single classic recipe using one of the four elements. A North Carolina barbecue pit master tutors him in the primal magic of fire; a Chez Panissetrained cook schools him in the art of braising; a celebrated baker teaches him how air transforms grain and water into a fragrant loaf of bread;...

Chemical Signals in Vertebrates 5
by D. W. Macdonald (Editor), D. Müller-Schwarze (Editor), S. E. Natynczuk (Editor)

This book is the fifth in a series on the subject of chemical signals, arising out of international conferences held every three years since 1976. This volume contains both substantial reviews and original research reports. Chemical cues and signals, usually in the form of odors, play a significant role in the lives of domestic and wild animals. Odors may attract or repel. They influence feeding and mating behavior, detection of predators and prey, social and spatial structure within groups, and the defense of territories. Biologists are continually refining their understanding of these phenomena and find ever more complex relationships among the chemical properties of the odor-producing substances, the physiological mechanisms of olfactory detection, and the behavioral responses of...

Chemical Signals in Vertebrates 1
by Dietland Muller-Schwarze (Editor)

Chemical Ecology of Insect Parasitoids
by Eric Wajnberg (Editor), Stefano Colazza (Editor)

Insect parasitoids are a fascinating group of animals in many respects. Perhaps the most fascinating point is that these insects, in the course of the evolutionary time, have developed an impressive way to use chemical compounds to dialogue with the different protagonists of their environment (i.e., conspecifics, their hosts and the plants on which their hosts are living). Unravelling the evolutionary meaning of such chemical communication networks can give new insights into the ecology of these insects and especially on how to improve their use for the control of noxious pests in biological control programmes.Chemical Ecology of Insect Parasitoids is a timely publication, with organised chapters to present the most important knowledge and discoveries that have taken place over the last...

Chemical Signals: Vertebrates and Aquatic Invertebrates
by Dietland Müller-Schwarze (Editor)

Chemical Signals in Vertebrates
by Dietland Müller-Schwarze (Editor), Maxwell M. Mozell (Editor)

The Paleo Solution: The Original Human Diet
by Robb Wolf (Author), Loren Cordain (Foreword)

Do you want to lose fat and stay young, all while avoiding cancer, diabetes, heart disease, Parkinson's, Alzheimer's and a host of other illnesses? The Paleo Solution incorporates the latest, cutting edge research from genetics, biochemistry and anthropology to help you look, feel and perform your best. Written by Robb Wolf, a research biochemist who traded in his lab coat and pocket protector for a whistle and a stopwatch to become one of the most sought after strength and conditioning coaches in the world. With Robb's unique perspective as both scientist and coach you will learn how simple nutrition, exercise and lifestyle changes can radically change your appearance and health for the better.

Signals and Boundaries: Building Blocks for Complex Adaptive Systems
by John H. Holland (Author)

Complex adaptive systems (cas), including ecosystems, governments, biological cells, and markets, are characterized by intricate hierarchical arrangements of boundaries and signals. In ecosystems, for example, niches act as semi-permeable boundaries, and smells and visual patterns serve as signals; governments have departmental hierarchies with memoranda acting as signals; and so it is with other cas. Despite a wealth of data and descriptions concerning different cas, there remain many unanswered questions about "steering" these systems. In Signals and Boundaries, John Holland argues that understanding the origin of the intricate signal/border hierarchies of these systems is the key to answering such questions. He develops an overarching framework for comparing and steering cas through...

Bombardier Beetles and Fever Trees: A Close-Up Look at Chemical Warfare and Signals in Animals and Plants
by William C. Agosta (Author)

Whether fighting off a hungry predator with an explosive burst of rocket fuel, or tantalizing a potential mate with a provocative perfume, organisms utilize built-in chemistry to go about their business. Animals and plants send each other warning signals and even broadcast calls for help, as well as create protective camouflage, make glue, lay trails, and poison their enemies. Bombardier Beetles and Fever Trees unravels the mystery behind these chemical weapons and communication schemes, providing a provocative study of the dynamic world of interspecies competition. In addition, author William Agosta discloses how we take advantage of many of the chemicals found in nature - from quinine, found in the bark of the fever tree and used to treat malaria, to taxol (from the Pacific yew), which...