A first step towards tailor-made drugs against the infectious disease
The tropical disease malaria is caused by the Plasmodium parasite. For its survival and propagation, Plasmodium requires a protein called actin. Scientists of the Helmholtz Centre for Infection Research (HZI) in Germany used high-resolution structural biology methods to investigate the different versions of this protein in the parasite in high detail.
Their results, published in the scientific journal “PLOS Pathogens”, may in the future contribute to the development of tailor-made drugs against malaria–a disease, that causes more than half a million deaths per year.
Malaria is a life-threatening disease. According to World Health Organization estimates, around 207 million cases of malaria occurred in 2012. Children in Africa are at an especially high risk, and there is no approved vaccination to date.
The disease is caused by Plasmodium parasites–single-celled parasites, which are transmitted by mosquitos. The pathogen enters the human body through a bite and induces typical symptoms like periodic fevers, nausea, and headaches.
To enter human cells and leave them again, the parasites need to be motile. To this end, they use a structural protein called actin. Actin is found in nearly all living organisms where it is one of the most abundant proteins. Inside cells, it assumes numerous tasks: It confers stability, allows cell division, and makes movement of single cells possible.
The dynamical behaviour needed for these processes is enabled by individual globular actin molecules assembling together to form thread-like structures called filaments. The malaria parasite possesses two versions of actin, actin I and actin II, which differ substantially from each other. Even though these structural proteins are crucial for the pathogen’s infectivity, researchers have so far not been able to demonstrate filament formation in the parasite.
Scientists of the HZI, the German Electron Synchrotron (DESY) and the European Molecular Biology Laboratory (EMBL), together with international partners, now succeeded in detecting filament assembly of the parasite actin II proteins. For this, they used electron microscopy, which overcomes the resolution limit of classical light microscopy.
Male malaria parasites from which the scientists had deleted actin II were not able to form mature germ cells and consequently could not reproduce and propagate. To have only one actin variant is apparently not sufficient for this process. How filaments contribute to germ cell maturation is still unclear. But why do the two proteins show such different behaviour?
To answer this question, the research team deciphered the structure of the globular actin proteins using X-radiation. “We were able to determine the structures of actin I and actin II at very high resolutions–down to 1.3 and 2.2 Ångström, respectively. With this, we are in the range of single atoms,” says the project leader Prof Inari Kursula.
“The structures show us that the two variants differ more from each other than actins in any other known living organism do.” The high resolution enabled the researchers to identify areas within the proteins that cause the different behaviour. “We now understand that Plasmodium actin filaments are very different from other actin filaments, like for example from those found in humans, and that they are assembled in a very different manner. Now that we know the structural basis for this, we can look for ways to specifically interfere with the parasite cytoskeleton,” says Kursula. This knowledge might in the future contribute to designing tailor-made anti-malarial medication.
Juha Vahokoski, Saligram Prabhakar Bhargav, Ambroise Desfosses, Maria Andreadaki, Esa-Pekka Kumpula, Silvia Muñico Martinez, Alexander Ignatev, Simone Lepper, Friedrich Frischknecht, Inga Sidén-Kiamos, Carsten Sachse, and Inari Kursula
Structural Differences Explain Diverse Functions of Plasmodium Actins
PLOS Pathogens, 2014, http://dx.plos.org/10.1371/journal.ppat.1004091
The junior research group “Structural Biology of the Cytoskeleton” at the interdisciplinary Centre for Structural Systems Biology (CSSB) investigates the cytoskeleton– a flexible network of proteins, which plays an important role in the motility and host cell entry of many pathogens. The scientists are especially interested in how Plasmodium, the malaria pathogen, uses its cytoskeleton for this purpose.
The Helmholtz Centre for Infection Research (HZI)
Scientists at the Helmholtz Centre for Infection Research in Braunschweig, Germany, are engaged in the study of different mechanisms of infection and of the body’s response to infection. Helping to improve the scientific community’s understanding of a given bacterium’s or virus’ pathogenicity is key to developing effective new treatments and vaccines.
Dr. Birgit Manno | Helmholtz-Zentrum
Colorectal cancer risk factors decrypted
13.07.2018 | Max-Planck-Institut für Stoffwechselforschung
Algae Have Land Genes
13.07.2018 | Julius-Maximilians-Universität Würzburg
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.
Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
13.07.2018 | Event News
13.07.2018 | Materials Sciences
13.07.2018 | Life Sciences