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Archive - Sep 28, 2009


Prion Proteins Appear to Share Evolutionary Origin with ZIP Proteins

Suggestive evidence as to the evolutionary ancestry of prion proteins has been obtained by researchers at the University of Toronto and collaborating institutions. Prions are responsible for such devastating diseases as “mad cow disease” (bovine spongiform encephalopathy) and Creutzfeldt-Jakob disease. The researchers’ analysis suggests that the prion gene is descended from the more ancient ZIP family of metal ion transporters. Members of the ZIP protein family are well known for their ability to transport zinc and other metals across cell membranes. The researchers initially demonstrated the physical proximity of two metal ion transporters, ZIP6 and ZIP10, to mammalian prion proteins in living cells. As with the normal cellular prion protein, ZIP6 and ZIP10 exhibit widespread expression in biological tissues with high transcript levels in the brain. The scientists then made the startling discovery that prion and ZIP proteins contain extensive stretches of similar amino acid sequence. The researchers next documented that the respective segments within ZIP and prion proteins are computationally predicted to acquire a highly similar three-dimensional structure. Finally, the team uncovered multiple additional commonalities between ZIP and prion proteins, which led them to conclude that these molecules are evolutionarily related. Overall, this work holds promise for efforts to reveal the physiological function of members of the prion protein family and may provide insights into the origins and underlying constraints of the conformational changes associated with prion diseases. This work was published on September 28 in PLoS ONE. [Press release] [PLoS ONE article]

Chemicals Prevent Premature Termination of Protein Synthesis in Genetic Disease

Using high-throughput screening of 35,000 compounds, scientists at UCLA have identified two compounds (nonaminoglycosides) that may have the potential to correct certain genetic diseases that are caused by the premature termination of protein synthesis due to nonsense mutations in the coding DNA. "When DNA changes, such as nonsense mutations, occur in the middle rather than the end of a protein-producing signal, they act like a stop sign that tells the cell to prematurely interrupt protein synthesis," explained Dr. Richard Gatti, senior author of the study. "These nonsense mutations cause the loss of vital proteins that can lead to deadly genetic disorders." Dr. Gatti's lab specializes in studying ataxia-telangiectasia (A-T), a progressive neurological disease that strikes young children, often killing them by their late teens or early 20s. "Of the dozens of active chemicals we discovered, only two were linked to the appearance and function of ATM, the protein missing from the cells of children with A-T," said Dr. Liutao Du, the first author of the study, in speaking about cellular studies that were conducted. "These two chemicals also induced the production of dystrophin, a protein that is missing in the cells of mice with a nonsense mutation in the muscular dystrophy gene." The UCLA team is optimistic that its discovery will aid pharmaceutical companies in creating drugs that correct genetic disorders caused by nonsense mutations. This could potentially affect one in five patients with most genetic diseases, including hundreds of thousands of people suffering from incurable diseases. Because nonsense mutations can lead to cancer, such drugs may also find uses in cancer treatment. This study was published in the September 28 issue of the Journal of Experimental Medicine.