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
Molecular Force Sensors
20.09.2017 | Max-Planck-Institut für Biochemie
Foster tadpoles trigger parental instinct in poison frogs
20.09.2017 | Veterinärmedizinische Universität Wien
Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...
Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!
When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...
For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.
Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...
MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems Holding GmbH about commercial use of a multi-well tissue plate for automated and reliable tissue engineering & drug testing.
MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems...
Pathogenic bacteria are becoming resistant to common antibiotics to an ever increasing degree. One of the most difficult germs is Pseudomonas aeruginosa, a...
19.09.2017 | Event News
12.09.2017 | Event News
06.09.2017 | Event News
20.09.2017 | Life Sciences
20.09.2017 | Power and Electrical Engineering
20.09.2017 | Physics and Astronomy