Scientists have long known that members of the phenoloxidase family are involved in skin and hair coloring. When they are mutated, they can cause albinism – the loss of coloring in skin and hair. Produced over abundantly, they are associated with the deadly skin cancer melanoma.
In an elegant structural study, a team of Baylor College of Medicine (www.bcm.edu) and German researchers explain how hemocyanin is activated – a finding that could lead to a better understanding of both ends of the skin and hair color spectrum. A report of their work appears in the current issue of the journal Structure.
When Dr. Yao Cong, a postdoctoral researcher in the laboratory of Dr. Wah Chiu (http://www.bcm.edu/biochem/?PMID=3715), displays the computer representation of hemocyanin, it glows like a four-part jewel on the computer screen (see Figure 1). Chiu is professor of biochemistry and molecular biology at BCM and director of the National Center for Macromolecular Imaging (http://ncmi.bcm.tmc.edu/ncmi/).
"It is very large and composed of 24 molecules," Cong said. In fact, it consists of four hexamers, each with six monomers (Movie 1 and Figure).
Just getting this far required using single particle electron cryomicroscopy (cryo-EM) to produce three dimensional density maps of the molecule at sub-nanometer resolution.
"Cryo-EM is becoming a structural tool that can be used for understanding structural mechanism of large protein, which has translational and biotechnological application as demonstrated in this study," said Chiu, a senior author.
"There are some critical structural features are very well resolved in our maps," said Cong. "which could not be captured using other techniques."
She and her colleagues used the detergent SDS, which is usually used as denaturant to degrade protein, to activate hemocyanin. At certain high concentrations, instead of destroyomg the complex, it turns hemocyanin into an enzymatically active phenoloxidase.
Each monomer of the protein particle has three domains.
"It is very interesting," said Cong. "One domain is more flexible than the other two domains because it has much less interaction with neighboring subunits as compared with the other two domains."
Upon activation, there is an overall conformational change of the complex (Movie 2). The most obvious is formation of two bridges in the previously vacant middle of the protein, which strengthens the interaction between the two halves of the complex.
"Zoom into the active site," said Cong. The intrinsically flexible domain twists away from the other two domains, dragging away a blocking residue and exposes the entrance to the active site (Movie 3). This movement is then stabilized by enhanced interhexamer interactions."
"This is all about interaction," said Cong. "A single change in the local domain of a subunit can result in conformation changes in the entire complex and make it work cooperatively. This is really a molecular machine."
Using hemocyanin as a model system, scientists can learn about the activation mechanism of other phenoloxidase enzymes in the same family, opening the door to new understanding of both melanoma and albinism, she said.
"If you know the mechanism of activating the protein, you could mutate it to enhance the interaction or inhibit it – depending on what you want to accomplish," she said.
Not only does this research have implications for human disease, it could also play a role in agriculture, where enzymes in this protein family are responsible for fruit and vegetables turning brown as they age.
Others who took part in this work include Qinfen Zhang, David Woolford, Htet Khant, Matthew Dougherty and Steven J Ludtke, all of BCM, and Thorsten Schweikardt and Heinz Decker of Johannes Gutenberg-University in Mainz, Germany. Zhang is now with Sun Yat-Sen University in Guangzhou, China, and Schweikardt is Boehringer Ingelheim Pharma GmbH & Co. in Germany.
Funding for this work came from the National Center for Research Resources, the Roadmap Initiative for Medical Research and the German Research Foundation and Research Center for Immunology in Mainz.
For more information on basic science research at Baylor College of Medicine, please go to www.bcm.edu/fromthelab
Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).
Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...
Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.
The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...
UMD, NOAA collaboration demonstrates suitability of in-orbit datasets for weather satellite calibration
"Traffic and weather, together on the hour!" blasts your local radio station, while your smartphone knows the weather halfway across the world. A network of...
Fiber-reinforced plastics (FRP) are frequently used in the aeronautic and automobile industry. However, the repair of workpieces made of these composite materials is often less profitable than exchanging the part. In order to increase the lifetime of FRP parts and to make them more eco-efficient, the Laser Zentrum Hannover e.V. (LZH) and the Apodius GmbH want to combine a new measuring device for fiber layer orientation with an innovative laser-based repair process.
Defects in FRP pieces may be production or operation-related. Whether or not repair is cost-effective depends on the geometry of the defective area, the tools...
10.01.2017 | Event News
09.01.2017 | Event News
05.01.2017 | Event News
16.01.2017 | Power and Electrical Engineering
16.01.2017 | Information Technology
16.01.2017 | Power and Electrical Engineering