The paper, available in and featured on the front cover of the Jan. 16, 2013, issue of FEBS Letters, a journal of the Federation of European Biochemical Societies, could broaden scientists' understanding of the importance of clathrin and potentially lead to new strategies for controlling cancer.
"This is a totally unexpected but wonderful finding," Ybe said. "It has exciting implications for understanding the role that clathrin may play in the growth or suppression of tumors."
Ybe is a senior research scientist in the Department of Molecular and Cellular Biochemistry in the IU College of Arts and Sciences. Co-authors of the paper are postdoctoral researchers Sarah Fontaine and Xiaoyan Lin; IU chemist Todd Stone; Sanjay Mishra, formerly at IU and now at Vanderbilt University; and Jay Nix of Lawrence Berkeley National Laboratory.
Typically found in a three-legged form called a trimer, clathrin is best understood for its role in endocytosis, the process by which cells absorb proteins and other molecules. But recent research has suggested that clathrin in a one-legged form, or monomer, may have a role in suppressing tumors. Ybe and his team show how a "switch" in clathrin can be flipped to produce non-trimeric clathrin molecules.
"Clathrin is known to function as a trimer in receptor-mediated endocytosis, but the existence of the monomeric form and its role in tumor suppression is less well-accepted," said Alexandra Ainsztein, who oversees membrane trafficking grants at the National Institute of General Medical Sciences of the National Institutes of Health. "By providing evidence for a model in which a molecular shift de-trimerizes clathrin and changes its cellular distribution, this work will spur further research into unanticipated roles for this important molecule in healthy and diseased cells."
In endocytosis, trimeric clathrin molecules bind together to form molecular packages that allow other substances to enter cells. Several years ago, researchers in Japan published evidence that clathrin can also serve as an activator of the protein p53, a known tumor suppressor.
For the activation to take place, clathrin and p53 must both be present in the cell's nucleus. The catch is that clathrin molecules cannot penetrate the nucleus in their usual, three-legged form. To enter, the three-legged clathrin molecule must be altered or "de-trimerized."
Using X-ray crystallography, Ybe and his team discovered a "topology switch" in the clathrin molecule. They showed they could break the switch by mutating one key amino acid that is part of the switch. The result: Clathrin was "detrimerized"; three-legged molecules were broken into one-legged ones.
Experimenting with both cancer and non-cancer cells, the researchers found the three-legged clathrin only in the cytoplasm of the cells, not the nucleus. But with the "switch" broken, clathrin formed monomers and was also present in the nucleus, where it could potentially activate tumor suppression.
Ybe said the results point to the need for additional research to better understand the structure and function of clathrin and the role it plays in cellular processes, including those involved in cancer. With the clathrin "switch" identified, researchers can attempt to better understand how it can be activated, with the goal of developing new therapies for suppressing the growth of tumors. Ybe has a patent pending on the idea to use the mutated form of clathrin to stimulate the natural anti-cancer activities of human cells.
The finding developed from Ybe's research on the role of clathrin in Huntington's disease, a genetic disorder that causes neurological degeneration and is estimated to affect about 15,000 people in the U.S. The National Institutes of Health awarded the project a $1.2 million, four-year grant in 2009. The NIH grant number is R01GM064387.
The article is available online. To speak with Ybe, please contact Steve Hinnefeld, IU Communications, 812-856-3488 or email@example.com
Steve Hinnefeld | EurekAlert!
Hunting pathogens at full force
22.03.2017 | Helmholtz-Zentrum für Infektionsforschung
A 155 carat diamond with 92 mm diameter
22.03.2017 | Universität Augsburg
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
22.03.2017 | Materials Sciences
22.03.2017 | Physics and Astronomy
22.03.2017 | Materials Sciences