University of Oregon researchers have identified protein interactions that regulate the response of cells to steroid hormones. The discovery, they say, could lead to new ways to boost the effectiveness and reduce undesired side effects of steroid-hormone treatments and cancer drugs.
The study, published online this week ahead of regular publication in the Proceedings of the National Academy of Sciences, also uncorks an almost 15-year bottleneck in research caused by difficulties in deciphering the actions of a heat-shock protein known as Hsp90.
Hsp90 belongs to a family of proteins called chaperones that help other proteins achieve and maintain their 3-D structure. Unlike most chaperones, Hsp90 is dedicated to assist a restricted yet diverse group of regulatory proteins, such as the glucocorticoid receptor, which requires help from Hsp90 to interact with hormones. Scientists had been stymied with how Hsp90 recognizes and interacts with client proteins.
Glucocorticoids are naturally produced by the adrenal glands and are important for a variety of tissue-related activities. They are immune-suppressive and anti-inflammatory, and are prescribed for such conditions as adrenal insufficiency as in Addison's disease, arthritis, asthma, inflammatory bowel disease and childhood acute lymphoblastic leukemia.
"Glucocorticoids are very commonly used in the treatment of diseases," Darimont said. "They have a bunch of physiological activities and functions, and responses are very different depending on the cells involved. The treatments are extremely effective, and glucocorticoids have been used in huge amounts in the last 40 years. Unfortunately, they are associated with very severe side effects. "
Side effects include osteoporosis, cataracts, ulcers, hypertension, impaired wound healing, diabetes and depression. Thus narrowing the point of attack, such as by manipulating Hsp90-glucocorticoid receptor interaction, is of growing importance, Darimont said.
The PNAS paper and a second publication that is under review cover the identification of the features of the glucocorticoid receptor (GR) recognized by Hsp90 and two sites on Hsp90 that interact with GR. To identify these sites, Darimont's team investigated 49,000 randomly introduced GR mutants and 11 specifically designed Hsp90 mutants for their binding and activation abilities. Finding and confirming the two binding sites were boosted by the recently published crystallized structures of both Hsp90 and GR, Darimont said.
"Our results suggest that Hsp90 binds GR with the help of specific docking sites in the C-terminal domain of Hsp90," she said. "This finding opens the possibility to develop small molecules that block specific Hsp90-client protein interactions. As part of our work, we also have identified GR mutants that are able to bind hormones without Hsp90, which may facilitate the development of novel synthetic glucocorticoids."
Jim Barlow | EurekAlert!
Staying in Shape
16.08.2018 | Max-Planck-Institut für molekulare Zellbiologie und Genetik
Chips, light and coding moves the front line in beating bacteria
16.08.2018 | Okinawa Institute of Science and Technology (OIST) Graduate University
Scientists at the University of California, Los Angeles present new research on a curious cosmic phenomenon known as "whistlers" -- very low frequency packets...
Scientists develop first tool to use machine learning methods to compute flow around interactively designable 3D objects. Tool will be presented at this year’s prestigious SIGGRAPH conference.
When engineers or designers want to test the aerodynamic properties of the newly designed shape of a car, airplane, or other object, they would normally model...
Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.
Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....
Proteins must be folded correctly to fulfill their molecular functions in cells. Molecular assistants called chaperones help proteins exploit their inbuilt folding potential and reach the correct three-dimensional structure. Researchers at the Max Planck Institute of Biochemistry (MPIB) have demonstrated that actin, the most abundant protein in higher developed cells, does not have the inbuilt potential to fold and instead requires special assistance to fold into its active state. The chaperone TRiC uses a previously undescribed mechanism to perform actin folding. The study was recently published in the journal Cell.
Actin is the most abundant protein in highly developed cells and has diverse functions in processes like cell stabilization, cell division and muscle...
Scientists have discovered that the electrical resistance of a copper-oxide compound depends on the magnetic field in a very unusual way -- a finding that could help direct the search for materials that can perfectly conduct electricity at room temperatur
What happens when really powerful magnets--capable of producing magnetic fields nearly two million times stronger than Earth's--are applied to materials that...
08.08.2018 | Event News
27.07.2018 | Event News
25.07.2018 | Event News
16.08.2018 | Life Sciences
16.08.2018 | Earth Sciences
16.08.2018 | Life Sciences