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Unique Role of Cell Death Protein TRADD in Viral Signaling

15.01.2008
Epstein-Barr virus is incredibly common in humans; up to 95% of adults in the developed world have been infected, which causes glandular fever and has been linked to the development of several forms of cancer. Research published in this week’s PLoS Biology investigates the way that the virus manipulates TRADD—a human protein—in order to establish itself in the host.

Epstein-Barr virus alters the way cells in the human immune system, called B lymphocytes, behave, transforming them into cancerous cells that survive and divide more than they should. It seems strange that TRADD can be involved in transforming cells to do this, because in a healthy person, TRADD is important in doing just the opposite: it causes apoptosis—organized cell death.

Researchers based in the GSF – National Research Centre for Environment and Health (from 2008: Helmholtz Zentrum Muenchen), in Munich, studied the way that TRADD interacts with LMP1, a protein produced by the virus that is essential for cell transformation. They genetically altered cells so that they wouldn’t produce any TRADD and found that these cells didn’t respond to the transformation signals sent by the LMP1 protein, showing that TRADD is necessary for this change. They studied the shape of the viral protein LMP1, and showed that a region of it binds to TRADD in a unique way. When TRADD is bound to LMP1, it is unable to interact with the molecules that it normally would, and so it cannot cause cell death as it is meant to.

The researchers, led by Dr. Arnd Kieser, took the unique TRADD binding site that they had identified on the viral protein and used it to replace the TRADD binding site on the host cellular protein that mediates cell death. This was enough to convert the cellular protein into a non-apoptotic receptor and thus to stop TRADD from inducing apoptosis. This is excellent evidence that they have correctly identified the mechanism that the viral protein uses to transform B lymphocytes.

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»LMP1 »Syn »TRADD »formation

“It is amazing to learn which sophisticated molecular means this human tumor virus has developed to take control of the communication system of its host cell,” Kieser said. “The unique interaction of LMP1 with TRADD could serve as a target structure for drug development against EBV-induced cancers.”

Conformational Equilibria in Monomeric a-Synuclein at the Single-Molecule Level

Natively unstructured proteins defy the classical “one sequence-one structure” paradigm of protein science. In pathological conditions, monomers of these proteins can aggregate in the cell, a process that underlies neurodegenerative diseases such as Alzheimer and Parkinson. A key step in the aggregation process, the formation of misfolded intermediates, remains obscure. This week in the open-access online journal PLoS Biology, researchers Luigi Bubacco, Bruno Samori and colleagues characterized the folding and conformational diversity of ?Syn, a natively unstructured protein involved in Parkinson disease, by mechanically stretching single molecules of this protein and recording their mechanical properties. These experiments permitted them to directly observe and quantify three main classes of conformations that, under in vitro physiological conditions, exist simultaneously in the ?Syn sample. They found that one class of conformations, “?-like” structures, is directly related to ?Syn aggregation. In fact, their relative abundance increases drastically in three different conditions known to promote the formation of ?Syn fibrils. They expect that a critical concentration of ?Syn with a “?-like” structure must be reached to trigger fibril formation. This critical concentration is therefore controlled by a chemical equilibrium. Novel pharmacological strategies can now be tailored to act upstream, before the aggregation process ensues, by targeting this equilibrium. To this end, Single Molecule Force Spectroscopy can be an effective tool to tailor and test new pharmacological agents.

Citation: Sandal M, Valle F, Tessari I, Mammi S, Bergantino E, et al. (2008) Conformational equilibria in monomeric a-synuclein at the single-molecule level. PLoS Biol 6(1): e6.doi:10.1371/journal.pbio.0060006

CONTACT:
Bruno Samori
University of Bologna
Department of Biochemistry
Bologna, 40126
Italy
+39 05 12 09 43 87
bruno.samori@unibo.it

Andrew Hyde | alfa
Further information:
http://www.plosbiology.org
http://biology.plosjournals.org/perlserv/?request=get- document&doi=10.1371/journal.pbio.0060006

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