Structure from disorder: Scientists find new source of versatility so ‘floppy’ proteins can get things done

June 19, 2013 — Many proteins work like Swiss Army knives, fitting multiple functions into their elaborately folded structures. A bit mysteriously, some proteins manage to multitask even with structures that are unfolded and floppy — “intrinsically disordered.” In this week’s issue of Nature, scientists at The Scripps Research Institute (TSRI) report their discovery of an important trick that a well-known intrinsically disordered protein (IDP) uses to expand and control its functionality.”We’ve found what is probably a general mechanism by which IDPs modulate their activities,” said TSRI Professor Peter E. Wright, who is Cecil H. and Ida M. Green Investigator in Biomedical Research and member of TSRI’s Skaggs Institute for Chemical Biology. Wright was a senior investigator for the study, along with TSRI Associate Professor Ashok A. Deniz.The study focused on an IDP known as the adenovirus “early region 1A oncoprotein” (E1A). An adenovirus starts producing copies of E1A shortly after it infects a cell. E1A proteins interact with a variety of key cellular molecules to quickly subvert the cell’s replication machinery for the benefit of the virus.Links to DiseaseE1A is worth studying not just because it facilitates adenovirus infections, but also because it’s a prime example of an IDP. Such proteins frequently play outsized roles in cells, as crucial “molecular hubs” within very large protein-interaction networks. …

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Self-fertilizing plants contribute to their own demise

June 10, 2013 — Many plants are self-fertilizing, meaning they act as both mother and father to their own seeds. This strategy — known as selfing — guarantees reproduction but, over time, leads to reduced diversity and the accumulation of harmful mutations. A new study published in the scientific journal Nature Genetics shows that these negative consequences are apparent across a selfing plant’s genome, and can arise more rapidly than previously thought.In the study, an international consortium led by Stephen Wright in the Department of Ecology and Evolutionary Biology at the University of Toronto sequenced the genome of the plant species Capsella rubella, commonly known as Red Shepherd’s Purse. They found clear evidence that harmful mutations were accumulating over the species’ relatively short existence.”The results underscore the long-term advantages of outcrossing, which is the practice of mating between individuals, that gives us the wide array of beautiful flowers,” said Wright. “Selfing is a good short-term strategy but over long timescales may lead to extinction.”Red Shepherd’s Purse is a very young species that has been self-fertilizing for less than 200,000 years. It is therefore especially well-suited for studying the early effects of self-fertilization. By contrasting Red Shepherd’s Purse with the outcrossing species that gave rise to it, the researchers showed that self-fertilization has already left traces across the genome of Red Shepherd’s Purse.”Harmful mutations are always happening,” said Wright. “In crops, they could reduce yield just as harmful mutations in humans can cause disease. The mutations we were looking at are changes in the DNA that change the protein sequence and structure.”The findings represent a major breakthrough in the study of self-fertilization.”It is expected that harmful mutations should accumulate in selfing species, but it has been difficult to support this claim in the absence of large-scale genomic data,” says lead author Tanja Slotte, a past member of Wright’s research team and now a researcher at Uppsala University. “The results help to explain why ancient self-fertilizing lineages are rare, and support the long-standing hypothesis that the process is an evolutionary dead-end and leads to extinction.”The researchers said that with many crops known to be self-fertilizing, the study highlights the importance of preserving crop genetic variation to avoid losses in yield due to mutations accumulating.

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New screening technique paves the way for protein drugs from bacteria

June 5, 2013 — A cheaper, more efficient technique for developing complex protein drugs from bacteria has been developed at the University of Sheffield.Using the bacterium E. coli, researchers from the University’s Faculty of Engineering showed it was possible to vastly increase the efficiency of the cells producing specifically modified proteins, as well as improve its performance and stability. The modification is present in over two-thirds of human therapeutic drugs on the market and involves the addition of specific sugar groups to the protein backbone, a process termed glycosylation.Drugs based on proteins are increasingly important in modern medicine to tackle health problems including diabetes, cancer and arthritis.Although simple proteins are traditionally made in microbial cells, these types of complex drugs are made using animal cells because they can make human-type glycosylations that will control its efficacy and stability in the body, and avoid immunogenic reactions in patients.Using bacteria to make proteins for use as medicines could be a more cost effective alternative, since using animal cells is expensive. However, the efficiency of glycoprotein production in bacterial cells is still very poor, with yields often several thousand times lower than in animal cells.Now, researchers in the Department of Chemical and Biological Engineering at the University of Sheffield, with collaboration from the University of Colorado, are using a technique called inverse metabolic engineering, that allows them to screen cells to identify strains that are likely to be the most efficient glycoprotein producers. Using this method, the team were able to produce seven times as much of the protein in laboratory tests.The team then used mass spectrometry to characterise and accurately quantify the proteins being produced by the bacteria. This allowed them to pinpoint modifications that will enable them, ultimately, to improve the performance of the drug.Professor Phil Wright, who led the research, said: “We believe that this technique will pave the way for pharmacologists to get the same protein yield from bacteria cells as they could from animal cells and also enable them to produce drugs from bacteria that have vastly improved focus and accuracy.”The team also tested the technique on antibody fragments with positive results, showing that their approach could work in different proteins.

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