 |
|
UCSD study reveals the regulatory mechanism of key enzyme
September 21, 2007Protein kinase A involved in cardiac disease and breast cancer
Research conducted at the University of California, San Diego (UCSD) School of Medicine has shed new light on the structure and function of one of the key proteins in all mammalian cells, protein kinase A (PKA), an enzyme which plays an essential role in memory formation, communication between nerve cells, and cardiac function.
Utilizing a process called x-ray crystallography, the scientists solved the structure of the large PKA complex, revealing a totally new structure that shows PKA's amazing ability to function as a "scaffold," that supports and controls the release of chemicals involved in transmitting signals. The structure is shown in the September 21 issue of the journal Cell, featuring the study that describes the dynamic regulatory subunit of PKA.
PKA belongs to a large superfamily of proteins whose activity is regulated by an important small molecule, cyclic AMP (cAMP), in the cell. Protein kinases transmit chemical signals within the cell to regulate a host of functions, such as cell growth or metabolism. Certain protein kinases have been implicated in the uncontrolled growth of cells; for example, when PKA somehow stays "on," its prolonged activation can lead to cardiac disease and breast cancer.
By revealing its highly accurate three-dimensional structure, the UCSD scientists have shown how PKA is inhibited and activated by cAMP. PKA contains two components, the regulatory and catalytic subunits. When the subunits are together in the absence of cAMP, the signaling is turned off; when the two parts break apart after being activated by cAMP, PKA is turned on.
"We knew how the two subunits, the catalytic and regulatory subunits, looked as separate entities. But we didn't understand how they actually fit together and are activated by cAMP until we saw this structure," said Susan Taylor, Ph.D., Howard Hughes Medical Institute Investor and professor of pharmacology at UCSD School of Medicine, who headed the study.
Discovery of this enzyme's molecular structure may help researchers to design drugs that specifically block the protein kinase activity involved in cancer or cardiac disease.
"Scientists didn't really understand how the structure unfolded before now," said Taylor, adding that preventing the subunits from coming apart may be an effective way to inhibit diseases caused when PKA is activated and can't turn itself off. Taylor said the researchers were surprised at how much the structure changed when PKA is turned off. "The regulatory subunit opens up and literally wraps itself around the catalytic subunit, thus completely turning the signal off," she said.
Taylor is one of the world's leading experts on the cAMP-dependent protein kinase, an enzyme that serves as a prototype for the entire protein kinase family. This family of enzymes has more than 500 members that are critical for regulation in all multi-cellular organisms, such as humans.
Taylor's work in 1991 (reported in the July 26, 1991 issue of the journal Science) revealed the first-ever molecular structure of the catalytic subunit of a protein kinase, one involved in the action of adrenalin within cells. Understanding its structure was a sort of Rosetta stone for learning the structure of all protein kinases, because they all share certain fundamental characteristics.
University of California - San Diego
PKA belongs to a large superfamily of proteins whose activity is regulated by an important small molecule, cyclic AMP (cAMP), in the cell. Protein kinases transmit chemical signals within the cell to regulate a host of functions, such as cell growth or metabolism. Certain protein kinases have been implicated in the uncontrolled growth of cells; for example, when PKA somehow stays "on," its prolonged activation can lead to cardiac disease and breast cancer.
By revealing its highly accurate three-dimensional structure, the UCSD scientists have shown how PKA is inhibited and activated by cAMP. PKA contains two components, the regulatory and catalytic subunits. When the subunits are together in the absence of cAMP, the signaling is turned off; when the two parts break apart after being activated by cAMP, PKA is turned on.
"We knew how the two subunits, the catalytic and regulatory subunits, looked as separate entities. But we didn't understand how they actually fit together and are activated by cAMP until we saw this structure," said Susan Taylor, Ph.D., Howard Hughes Medical Institute Investor and professor of pharmacology at UCSD School of Medicine, who headed the study.
Discovery of this enzyme's molecular structure may help researchers to design drugs that specifically block the protein kinase activity involved in cancer or cardiac disease.
"Scientists didn't really understand how the structure unfolded before now," said Taylor, adding that preventing the subunits from coming apart may be an effective way to inhibit diseases caused when PKA is activated and can't turn itself off. Taylor said the researchers were surprised at how much the structure changed when PKA is turned off. "The regulatory subunit opens up and literally wraps itself around the catalytic subunit, thus completely turning the signal off," she said.
Taylor is one of the world's leading experts on the cAMP-dependent protein kinase, an enzyme that serves as a prototype for the entire protein kinase family. This family of enzymes has more than 500 members that are critical for regulation in all multi-cellular organisms, such as humans.
Taylor's work in 1991 (reported in the July 26, 1991 issue of the journal Science) revealed the first-ever molecular structure of the catalytic subunit of a protein kinase, one involved in the action of adrenalin within cells. Understanding its structure was a sort of Rosetta stone for learning the structure of all protein kinases, because they all share certain fundamental characteristics.
University of California - San Diego
Protein Kinase News and Current Protein Kinase Events RSSCancer therapy: A role for MAPK inhibitors combined with mTORC1 inhibitors
Nearly a decade ago, while it was being tested as an immunosuppressive agent to prevent organ rejection in transplant patients, the drug rapamycin was also discovered to have anti-tumor properties. Since then, several rapamycin analogs known as mTOR (mammalian target of rapamycin) inhibitors have been tested in clinical trials for the treatment of various types of cancer.
Study shows how daughter is different from mother
The mother-daughter relationship can be difficult to understand. Why are the two so different? Now a Northwestern University study shows how this happens. In yeast cells, that is.
USC researchers identify alternate pathway that leads to palate development
Researchers at the University Of Southern California School Of Dentistry have uncovered another clue behind the causes of cleft palate and the process that leads to palate formation.
Researchers discover link between organ transplantation and increased cancer risk
Researchers have determined a novel mechanism through which organ transplantation often leads to cancer, and their findings suggest that targeted therapies may reduce or prevent that risk.
Post-exercise caffeine helps muscles refuel
Recipe to recover more quickly from exercise: Finish workout, eat pasta, and wash down with five or six cups of strong coffee.
Novel enzyme inhibitor paves way for new cancer drug
Combining natural organic atoms with metal complexes, scientists at The Wistar Institute have developed a new type of enzyme inhibitor capable of blocking a biochemical pathway that plays a key role in cancer development.
Researchers report the cloning of a key group of human genes, the protein kinases
Although the human genome has been sequenced, research into mechanism of action of genes has been hampered by the fact that most human genes have not been isolated. This is true for even the most common class of cancer-associated genes, the protein kinases, which mediate the majority of signaling events in cells by phosphorylating and modulating the activity of other proteins.
Researcher discovers pathway plants use to fight back against pathogens
Plants are not only smart, but they also wage a good fight, according to a University of Missouri biochemist. Previous studies have shown that plants can sense attacks by pathogens and activate their defenses.
3 newly discovered ERK pathway proteins related to CagA induced disease
Cytotoxin-associated gene A protein (CagA) from type I H.pylori has been proved by epidemiological and experimental studies to be closely associated with the H.pylori induced gastric diseases, especially gastric cancer.
Novel compound may lessen heart attack damage
A novel drug designed to lessen muscle damage from a heart attack has passed initial safety tests at the Duke Clinical Research Institute. Results of the study, available online and to be published in the February 19 issue of the journal Circulation, reflect the first time the drug has been tested in humans.
More Protein Kinase News Articles
 | Protein Phosphorylation: A Practical Approach (Practical Approach Series) Reversible phosphorylation is one of the major mechanisms of controlling protein activity in all eukaryotic cells. This new edition of Protein Phosphorylation: A Practical Approach provides a comprehensive description of current methods used to study protein phosphorylation and the kinases and phosphatases which catalyse it. It includes protocols for studying phosphorylation in intact cells;... |
 | Protein Phosphatases (Topics in Current Genetics) This book provides an up-to-date and comprehensive overview of protein phosphatase research, a rapidly evolving field with increasing importance in our understanding of the molecular basis of cell biology and of pathological processes. The book covers dephosphorylation processes involving serine/threonine, as well as tyrosine and histidine residues, and aims to be a useful resource for both the... |
| Protein Kinase A and Human Disease (Annals of the New York Academy of Sciences) | |
| Vascular Complications of Diabetes: Current Issues in Pathogenesis and Treatment Diabetes has reached epidemic proportions, and the cardiovascular complications of diabetes are life-threatening and disabling. This book is unique in providing a simple explanation of the biochemical role of PKC in diabetes complications, which allows clinicians to understand why PKC inhibitors (in development) are an exciting prospect for future treatment to slow progression of eye & foot... | |
 | Protein Kinase Facts Book (Two-Volume Set) (Factsbook) by Grahame Hardie, Steven Hanks How do you keep track of basic information on the proteins you work with? Where do you find details of their physicochemical properties, amino acid sequences, gene organization? Are you tired of scanning review articles, primary papers and databases to locate that elusive fact?The Academic Press FactsBook series will satisfy scientists and clinical researchers suffering from information overload.... |
 | Methods in Enzymology, Volume 201: Protein Phosphorylation, Part B: Analysis of Protein Phosphorylation, Protein Kinase Inhibitors, and Protein (Methods in Enzymology) This volume provides a compilation of recent methods for studying protein... |
 | MAP Kinase Signaling Protocols (Methods in Molecular Biology) (Methods in Molecular Biology) An outstanding collection of both classic and cutting-edge techniques for the detection and measurement of mitogen-activated protein kinase (MAPK) signaling cascades. The protocols includes methods for the determination of the subcellular localization of these components, the structural and biophysical analysis of the components, and identification of novel components of known and unknown... |
 | Protein Tyrosine Kinases: From Inhibitors to Useful Drugs (Cancer Drug Discovery and Development) Leading researchers, from the Novartis group that pioneered Gleevec/Glivec™ and around the world, comprehensively survey the state of the art in the drug discovery processes (bio- and chemoinformatics, structural biology, profiling, generation of resistance, etc.) aimed at generating PTK inhibitors for the treatment of various diseases, including cancer. Highlights include a discussion of... |
 | TOR: Target of Rapamycin (Current Topics in Microbiology and Immunology) TOR, the Target of Rapamycin was discovered a little over ten years ago in a genetic screen in S. cerevisiae in search of mutants resistant to the cytostatic effects of the antimycotic, rapamycin. Recent studies have placed TOR at the interface between nutrient sensing and the regulation of major anbolic and catabolic responses. The editors have gathered the leading figures in the field of TOR... |
 | Creatine Kinase (Molecular Anatomy and Physiology of Proteins) |
| © 2008 BrightSurf.com |