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  • richardmitnick 10:29 am on November 26, 2015 Permalink | Reply
    Tags: , Protein Studies,   

    From TUM: “The “dark matter” in the protein universe” 

    Techniche Universitat Munchen

    Techniche Universitat Munchen

    Dr. Andrea Schafferhans
    Technical University of Munich
    Chair of Bioinformatics, Prof. Burkhard Rost
    Tel.: +49 289 17833

    Scientists try to reveal the structures of the dark proteome. (Picture: Schafferhans / Aquaria)

    Whether in the form of antibodies, enzymes or carriers: proteins play a crucial role in biology. While researchers have been able to at least partially determine the three-dimensional structure of many proteins, the structures of many other protein building blocks and even entire protein molecules remain as yet unknown. These “dark proteins” could be the key to understanding diseases. Using bioinformatics methods, an international team of scientists including researchers from the Technical University of Munich (TUM) has come one step closer to unveiling the mystery that surrounds the dark proteome. Protein research and biomedicine are two of TUM’s core research areas.

    Fifteen percent of the mass of an average human: that is the overall amount of all proteins, also known as the proteome. The protein molecules perform essential functions in the body and cells. They initiate metabolic processes, help the organism ward off diseases and ensure that vital biological substances are transported.

    The function of these proteins is significantly determined by their three-dimensional structure. Yet there are also proteins that either completely or at least partially differ from the structure that has so far been elucidated by scientific experiments. As a result, their structure cannot be modeled. Researchers refer to these proteins and protein building blocks as “dark proteins” and collectively as the “dark proteome”, in analogy to the dark matter found in outer space. Up until now, scientists still did not know how many of these proteins form part of the dark proteome.

    Half of the proteome is dark

    Together with the Commonwealth Scientific and Industrial Research Organisation (CSIRO) in Sydney and the University of Lisbon, Dr. Andrea Schafferhans from the Chair of Bioinformatics at TUM studied the properties of the dark proteome. They did so by filtering out pieces of information from various databases, linking them with each other and evaluating the data.

    The “Aquaria” database, a joint project organized by CSIRO and TUM, played an important role in this process. The website went live in early 2015 and allows all researchers to have the 3D structure of protein sequences computed. The database does this by referring to existing structures and using that information to create a probable model for the new structure. This website helps researchers determine which protein structures are in fact “dark”.

    The result: Half of the proteome of all living beings whose cells have a nucleus – and that includes humans – is part of the dark proteome. “And again half of that has structures that remain completely unidentified,” says Schafferhans.

    Few relatives, hardly any interactions with other proteins

    Furthermore, the researchers were able to identify the following properties of dark proteins: Most dark proteins are short, rarely interact with other proteins, are frequently excreted and only have a small number of evolutionary relatives.

    The scientists also found out that some of the assumptions previously held about dark proteins are in fact wrong. The majority of them are not disordered proteins, for example. The latter only adopt their actual structure once they perform a function. The remainer of the time they aopt varying shapes. Moreover, the majority of dark proteins are not transmembrane proteins, i.e. proteins located inside a membrane that separates cell components or entire cells from each other. Up until now, these two assumptions were believed to explain why the structure of dark proteins is so hard to identify.

    With their findings, which were published in the specialist journal Proceedings of the National Academy of Sciences, the researchers have laid important groundwork that will help scientists better analyze these mysterious protein molecules in the future.

    The researchers also hope to draw more attention to the dark proteome, because it could contain proteins that play a key role in human health.

    Medical protein research at TUM

    Biomedicine is a key research area at TUM, which consequently combines basic and applied research. As part of this concept, the following new research facilities were set up: the TUM Center for Functional Protein Assemblies (CPA), the Bavarian Nuclear Magnetic Resonance Center, the Central Institute for Translational Cancer Research of the Tech­nical University of Munich (TranslaTUM) and the Klaus Tschira Foundation’s Research Center for Multiple Sclerosis. As an integrative research center, TUM’s MUNICH SCHOOL OF BIOENGINEERING forms a joint learning and research platform for all pertinent activities carried out in medically relevant fields of engineering in the various faculties, including imaging technologies. TUM is also a major stakeholder in the Center for Integrated Protein Science Munich (CIPSM) cluster of excellence.

    Nelson Perdigãoa et al.: Unexpected features of the dark proteome. Proceedings of the National Academy of Sciences (2015). DOI: 10.1073/pnas.1508380112

    See the full article here .

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    Techniche Universitat Munchin Campus

    Technische Universität München (TUM) is one of Europe’s top universities. It is committed to excellence in research and teaching, interdisciplinary education and the active promotion of promising young scientists. The university also forges strong links with companies and scientific institutions across the world. TUM was one of the first universities in Germany to be named a University of Excellence. Moreover, TUM regularly ranks among the best European universities in international rankings.

  • richardmitnick 4:07 pm on November 24, 2015 Permalink | Reply
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    From ORNL: “New supercomputer simulations enhance understanding of protein motion and function” 


    Oak Ridge National Laboratory

    November 23, 2015
    Morgan McCorkle, Communications
    mccorkleml@ornl.gov, 865.574.7308

    Miki Nolin

    Illustration of the structure of a phosphoglycerate kinase protein that was subjected to molecular dynamics simulations. The relative motions of the red and blue domains of the proteins are highly complex, and can be described in terms of motion of a configurational point on a rough energy landscape (illustrated). The transitions of the structure between energy minima on the landscape can be described in terms of a network (illustrated), which is found to be fractal (self-similar) on every timescale. Image credit: Thomas Splettstoesser; http://www.scistyle.com

    Supercomputing simulations at the Department of Energy’s Oak Ridge National Laboratory could change how researchers understand the internal motions of proteins that play functional, structural and regulatory roles in all living organisms. The team’s results are featured in Nature Physics.

    “Proteins have never been seen this way before,” said coauthor Jeremy Smith, director of ORNL’s Center for Molecular Biophysics and a Governor’s Chair at the University of Tennessee (UT). “We used considerable computer power to provide a unified conceptual picture of the motions in proteins over a huge range of timescales, from the very shortest lengths of time at which atoms move (picoseconds) right up to the lifetimes of proteins in cells (roughly 1000 seconds). It changes what we think a protein fundamentally is.”

    Studying proteins—their structure and function—is essential to advancing understanding of biological systems relevant to different energy and medical sciences, from bioenergy research and subsurface biogeochemistry to drug design.

    Results obtained by Smith’s UT graduate student, Xiaohu Hu, revealed that the dynamics of single protein molecules are “self-similar” and out of equilibrium over an enormous range of timescales.

    With the help of Titan— the fastest supercomputer in the U.S., located at the DOE Office of Science’s Oak Ridge Leadership Computing Facility—Smith’s team developed a complete picture of protein dynamics, revealing that the structural fluctuations within any two identical protein molecules, even if coded from the same gene, turn out to be different.


    “A gene is a code for a protein, producing different copies of the protein that should be the same, but the internal fluctuations of these individual protein molecules may never reach equilibrium, or converge,” Smith said. “This is because the fluctuations themselves are continually aging and don’t have enough time to settle down before the protein molecules are eaten up in the cell and replaced.”

    Understanding the out-of-equilibrium phenomenon has biological implications because the function of a protein depends on its motions. Two individual protein molecules, even though they come from the same gene, will not function precisely the same way within the cell.

    “You may have, for example, two identical enzyme molecules that catalyze the same reaction,” said Smith. “But due to the absence of equilibrium, the rate at which the catalysis happens will be slightly different for the two proteins. This affects the biological function of the protein.”

    The team also discovered that the dynamics of single protein molecules are self-similar, or fractal over the whole range of timescales. In other words, the motions in a single protein molecule look the same however long you look at them for, from picoseconds to hundreds of seconds.

    “The motions in a protein, how the bits of the protein wiggle and jiggle relative to each other, resemble one another on all these timescales,” Smith said. “We represent the shape of a protein as a point. If it changes its shape due to motions, it goes to a different point, and so on. We joined these points, drawing pictures, and we found that these pictures are the same when you look at them on whatever timescale, whether it’s nanoseconds, microseconds, or milliseconds.”

    By building a more complete picture of protein dynamics, the team’s research reveals that motions of a single protein molecule on very fast timescales resemble those that govern the protein’s function.

    To complete all of the simulations, the team combined the power of Titan with two other supercomputers—Anton, a specialty parallel computer built by D.E. Shaw Research, and Hopper, the National Energy Research Scientific Computing Center’s Cray XE6 supercomputer located at Lawrence Berkeley National Laboratory.



    “Titan was especially useful for us to get accurate statistics,” Smith said. “It allowed us to do a lot of simulations in order to reduce the errors and get more confident results.”

    The title of the Nature Physics paper is The Dynamics of Single Protein Molecules is Non-Equilibrium and Self-Similar Over Thirteen Decades in Timehttp://www.nature.com/nphys/journal/vaop/ncurrent/full/nphys3553.html

    This research was supported by the DOE Office of Science through an Advanced Scientific Computing Research (ASCR) Leadership Computing Challenge (ALCC) allocation and funded in part by a DOE Experimental Program to Stimulate Competitive Research (EPSCoR) award. The Oak Ridge Leadership Computing Facility and National Energy Research Scientific Computing Center are DOE Office of Science User Facilities.

    See the full article here .

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    ORNL is managed by UT-Battelle for the Department of Energy’s Office of Science. DOE’s Office of Science is the single largest supporter of basic research in the physical sciences in the United States, and is working to address some of the most pressing challenges of our time.


  • richardmitnick 8:57 am on October 16, 2015 Permalink | Reply
    Tags: , , Protein Studies, U Illinois   

    From U Illinois: “COMPASS method points researchers to protein structures” 

    U Illinois bloc

    University of Illinois

    Oct 9, 2015
    Liz Ahlberg

    Graduate student Joseph Courtney and chemistry professor Chad Rienstra developed a method to quickly and reliably determine a protein’s intricately folded structure. Photo by L. Brian Stauffer

    Searching for the precise, complexly folded three-dimensional structure of a protein can be like hacking through a jungle without a map: a long, intensive process with uncertain direction. University of Illinois researchers developed a new approach, dubbed COMPASS, that points directly to a protein’s likely structure using a combination of advanced molecular spectroscopy techniques, predictive protein-folding algorithms and image recognition software.

    Led by U. of I. chemistry professor Chad Rienstra, the team published its results in the journal Structure.

    “We’ve taken a process that would take months and brought it down to hours,” said Joseph Courtney, an Illinois graduate student and first author of the paper. “We expect this to not only accelerate the rate at which we can study proteins, but also increase its repeatability and the reliability of the results.”

    Proteins carry out functions within the cell, and those functions are determined by the proteins’ precise structures – the way they fold and twist into an intricate three-dimensional shape.

    “Many diseases are caused by a protein that’s not acting correctly, or there is too much of it. If you can understand what the proteins look like, you can study how they work, and you can help design drugs and treatments for those diseases,” Courtney said. “A major benefit is that if you can design a drug to perfectly fit a single protein, that cuts down on side effects, because it won’t interact with other molecules.”

    One key method for determining a protein’s share is a technique called X-ray crystallography. However, many medically interesting proteins – for example, the fibrils that characterize Parkinson’s disease – do not form crystals, so researchers have turned to more advanced spectroscopic techniques. Those techniques require months to years of intensive data collection and analysis, taking numerous readings and measurements of the protein’s spectrum.

    The Illinois team saw an opportunity to take advantage of recent advances in structure prediction algorithms, computational models that generate numerous possible ways a protein could fold based on its sequence.

    “The major shortcoming of those modeling approaches is that they never know if they’re right,” Rienstra said. “It’s great to have models, but it still leaves thousands of possibilities. We need some type of experimental data to determine which is the right one.”

    For COMPASS, the researchers rely on a single spectrum measurement using a spectroscopic technique called nuclear magnetic resonance, which gives a molecular “fingerprint” – no two protein structures have the same spectrum.

    The COMPASS platform looks at the possible structures generated by the predictive models, projects a spectrum for each one, and uses advanced image-recognition software to compare each projected spectrum with the spectrum collected from the experimental sample.

    “We call it COMPASS because we’re using a magnetic field to hopefully point us in the right direction of which protein structure is the right one out of all these options,“ Rienstra said.

    The researchers compared COMPASS results of 15 proteins to the structure information determined from traditional methods, and found that COMPASS was successful in correctly determining the proteins’ structures.

    The researchers hope that other chemists will adopt the COMPASS method. One advantage, Rienstra said, is that a chemist does not have to be an expert to use COMPASS, as the results from the algorithms are automatic, objective and repeatable.

    Rienstra’s group plans to use COMPASS in biomedical applications, hoping to study proteins that have thus far eluded researchers because of structural complexity and scarcity of samples.

    “We already have collaborators sending us samples to compare,” Rienstra said. “We’re working to compare the samples of a protein from Parkinson’s disease patients with the sample we study in the lab, to see if it’s the same in their brains as it is when we make it in the lab. That’s a very important question to address. The samples are very small and the signals are weak, but we can get one spectrum and see if the structures match. This would be impossible with traditional approaches because we would need brain samples a hundred times larger, and you just can’t do that with human patients.”

    “The normal bottleneck of collecting and analyzing the data is now completely gone,” Courtney said. “What would be an entire thesis project for a graduate student can now be reduced to a day. And as the prediction algorithms get better, COMPASS will be able to take advantage of those advances to help find even more difficult protein structures.”

    The National Institutes of Health supported this work.

    See the full article here .

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    The University of Illinois at Urbana-Champaign community of students, scholars, and alumni is changing the world.

    With our land-grant heritage as a foundation, we pioneer innovative research that tackles global problems and expands the human experience. Our transformative learning experiences, in and out of the classroom, are designed to produce alumni who desire to make a significant, societal impact.

  • richardmitnick 1:48 pm on October 15, 2015 Permalink | Reply
    Tags: , , Protein Studies,   

    From TUM: “New field of application for versatile helper” 

    Techniche Universitat Munchen

    Techniche Universitat Munchen

    Prof. Dr. Bernd Reif
    Technical University of Munich
    Solid State NMR Spektroscopy
    Lichtenbergstr 4, 85747 Garching, Germany
    Tel.: +49 89 289 13667

    Space-filling model of alphaB crystallin. The hexameric subunit is indicated in color – Image: Andi Mainz / TUM

    Small heat shock protein as model for Alzheimer medication

    In Alzheimer’s disease proteins clump together to long fibrils causing the death of nerve cells. Small heat shock proteins can counteract this effect. Scientists, therefore, hope to deploy them as agents in the treatment of neurodegenerative diseases. Using the example of a small heat shock protein, researchers at the Technical University of Munich (TUM) and the Helmholtz Zentrum München have now uncovered how the protein interacts with other proteins.

    Small heat shock proteins are the “catastrophe aid workers” of the cell. When exposed to strong heat or radiation, vital cell proteins lose their structure and clot up to entangled clumps. Once these clumps have formed there is no return – the proteins become useless and the cells begin to die. Small heat shock proteins, however, attach to the deformed proteins before they clump together and preserve them in a soluble state – helping to restore their proper form.

    Promising candidate for new forms of therapy

    The helper proteins are true multi-talents. They can bind large numbers of badly folded proteins and keep them from clumping together. This also includes the potentially disease-causing proteins that collect in the cells of patients with neurodegenerative disorders – for example, beta amyloids that agglomerate to form long fibrils in the nerve cells of Alzheimer’s patients. Heat shock proteins are also associated with other nervous system disorders like Parkinson’s disease and multiple sclerosis.

    Although it is still unclear what role these catastrophe aid workers play in the various ailments, they are already being considered as models for agents in new medications. If the precise mechanisms by which these heat shock proteins hook up to their disease-causing counterparts were known, scientists could deploy this knowledge to develop agents utilizing these mechanisms to fight disease.

    Two ways out of the chaos

    A group of researchers led by Bernd Reif, professor at the Department of Chemistry of the Technical University of Munich (TUM) and group leader at the Helmholtz Zentrum München, have now succeeded in uncovering precisely this mechanism. Using a refined procedure of solid-state nuclear magnetic resonance spectroscopy (solid-state NMR), they managed, for the first time ever, to identify the sites in the alpha-B-crystallin that attach to the beta-amyloid.

    It is the first direct structure analysis of a complete heat shock protein during interaction with a bonding partner, because the catastrophe aid workers do not make the observer’s job easy. “Alpha-B-crystallin exists in various different forms comprising 24, 28 or 32 subunits that are permanently being swapped,” explains Reif. “In addition, it has a large molecular weight. These factors make structure analysis very difficult.”

    In close collaboration with his TUM colleagues Johannes Buchner, professor of biotechnology and Sevil Weinkauf, professor of electron microscopy, Reif determined that the small heat shock protein uses a specific non-polar beta-sheet structure pile in its center for interactions with the beta-amyloid, allowing it to access the aggregation process in two locations at once: For one it attaches to individual dissolved beta-amyloids, preventing them from forming fibrils. In addition, it “seals” existing fibrils, so that further amyloids can no longer accumulate.

    Template for artificial protein construction

    Precise knowledge about the way in which alpha-B-crystallin attaches to the Alzheimer’s protein is particularly interesting for researchers using so-called protein engineering to develop new agents that bind specifically to beta-amyloid and similar proteins. If the newly discovered beta-sheet structure idea could be integrated as building blocks into such artificially designed proteins, it would improve their ability to attach to the disease-causing fibrils – a first step in the development of new agents against Alzheimer’s and other neurodegenerative diseases.

    In future work, the scientists want to take a closer look at the N-terminal region of the alpha-B-crystallin. As Reif and his colleagues have discovered, it binds protein types that, unlike the beta-amyloid, clump together in an unordered manner. The researchers will be supported by the new NMR Center that is currently under construction at the Garching campus of the Technical University of Munich and slated to open in 2017. A further 5 million euro facility geared specifically to solid-state NMR is currently under construction at the Helmholtz Zentrum in Neuherberg.

    The research was funded by the Helmholtz Zentrum München and the German Research Foundation (DFG) (SFB-1035 and the Excellence Cluster “Center for Integrated Protein Science Munich” (CIPSM)).


    Andi Mainz, Jirka Peschek, Maria Stavropoulou, Katrin C. Back, Benjamin Bardiaux, Sam Asami, Elke Prade, Carsten Peters, Sevil Weinkauf, Johannes Buchner, Bernd Reif: The Chaperone alpha B-Crystallin Deploys Different Interfaces to Capture an Amorphous and an Amyloid Client,
    Nature Structural Molecular Biology, Oct. 12, 2015; DOI: 10.1038/nsmb.3108

    See the full article here .

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    Techniche Universitat Munchin Campus

    Technische Universität München (TUM) is one of Europe’s top universities. It is committed to excellence in research and teaching, interdisciplinary education and the active promotion of promising young scientists. The university also forges strong links with companies and scientific institutions across the world. TUM was one of the first universities in Germany to be named a University of Excellence. Moreover, TUM regularly ranks among the best European universities in international rankings.

  • richardmitnick 2:08 pm on April 7, 2015 Permalink | Reply
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    From MedicalXpresss: “Food for thought: Master protein enhances learning and memory” 

    Medicalxpress bloc


    April 7, 2015
    No Writer Credit

    Salk researchers and collaborators discovered that physical and mentalactivities rely on a single metabolic protein, ERRγ, that controls theflow of blood and nutrients throughout the body. In this image, ERRγ isshown (stained red) in the hippocampus, the area of the brain largely responsible for memory. The new work could point to a way to enhance learning. Credit: Salk Institute

    Just as some people seem built to run marathons and have an easier time going for miles without tiring, others are born with a knack for memorizing things, from times tables to trivia facts. These two skills ― running and memorizing ― are not so different as it turns out.

    Salk scientists and collaborators have discovered that physical and mental activities rely on a single metabolic protein that controls the flow of blood and nutrients throughout the body, as reported in the journal Cell Metabolism. The new study could point to potential treatments in regenerative and developmental medicine as well as ways to address defects in learning and memory.

    “This is all about getting energy where it’s needed to ‘the power plants’ in the body,” says Ronald Evans, director of Salk’s Gene Expression Laboratory and senior author of the new paper, published April 7, 2015.”The heart and muscles need a surge of energy to carry out exercise and neurons need a surge of energy to form new memories.”

    Energy for muscles and brains, the scientists discovered, is controlled by a single protein called estrogen-related receptor gamma (ERRγ). Evans’research group has previously studied the role of ERRγ in the heart and skeletal muscles. In 2011, they discovered that promoting ERRγ activity int he muscle of sedentary mice increased blood supply to their muscles and doubled their running capacity. ERRγ, they went on to show, turns on a whole host of muscle genes that convert fat to energy.

    Thus, ERRγ became known as a master metabolic switch that energized muscle to enhance performance. Although studies had also shown that ERRγ was active in the brain, researchers didn’t understand why ― the brain burns sugar and ERRγ was previously shown to only burn fat. So the team decided to look more closely at what the protein was doing in brain cells.

    By first looking at isolated neurons, Liming Pei, lead and co-corresponding author of the paper, found that, as in muscle, ERRγactivates dozens of metabolic genes in brain cells. Unexpectedly, this activation related to sugar instead of fat. Neurons that lacked ERRγ could not ramp up energy production and thus had a compromised performance.

    “We assumed that ERRγ did the same thing throughout the body,” says Evans.”But we learned that it’s different in the brain.” ERRγ, they now conclude, turns on fat-burning pathways in muscles and sugar-burning pathways in the brain.

    Evans and his collaborators noticed that ERRγ in live mice was most active in the hippocampus ― an area of the brain that is active in producing new brain cells, is involved in learning and memory and is known to require lots of energy. They wondered whether ERRγ had a direct role in learning and memory. By studying mice lacking ERRγ in the brain, they found a link.

    While mice without the protein had normal vision, movement and balance,they were slower at learning how to swim through a water maze ― and poor at remembering the maze on subsequent trials ― compared to mice with normal levels of ERRγ.

    “What we found is that mice that missing ERRγ are basically very slow learners,” says Pei. Varying levels of ERRγ could also be at the root of differences between how individual humans learn, he hypothesizes.”Everyone can learn, but some people learn and memorize more efficiently than others, and we now think this could be linked to changes in brain metabolism.”

    A better understanding of the metabolism of neurons could help point the way to improved treatments for learning and attention disorders. And possibly, revving up levels of ERRγ could even enhance learning, just as it enhances muscle function.

    “What we’ve shown is that memories are really built on a metabolic scaffold,” says Evans. “And we think that if you want to understand learning and memory, you need to understand the circuits that underlie and power this process.”

    See the full article here.

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    Medical Xpress is a web-based medical and health news service that is part of the renowned Science X network. Medical Xpress features the most comprehensive coverage in medical research and health news in the fields of neuroscience, cardiology, cancer, HIV/AIDS, psychology, psychiatry, dentistry, genetics, diseases and conditions, medications and more.

  • richardmitnick 5:57 am on March 10, 2015 Permalink | Reply
    Tags: , , , Protein Studies,   

    From Scripps: “TSRI Scientists Reveal Structural Secrets of Nature’s Little Locomotive” 


    Scripps Research Institute

    March 9, 2015
    No Writer Credit

    Findings Could Help Shed Light on Alzheimer’s, Parkinson’s, ALS and Other Diseases

    A team led by scientists at The Scripps Research Institute (TSRI) has determined the basic structural organization of a molecular motor that hauls cargoes and performs other critical functions within cells.

    The new research provides the first picture of a molecular motor called the “dynein-dynactin complex,” which is critical for cell division and cargo transport. (Image courtesy of the Lander lab, The Scripps Research Institute.)

    Biologists have long wanted to know how this molecular motor—called the “dynein-dynactin complex”—works. But the complex’s large size, myriad subunits and high flexibility have until now restricted structural studies to small pieces of the whole.

    In the new research, however, TSRI biologist Gabriel C. Lander and his laboratory, in collaboration with Trina A. Schroer and her group at Johns Hopkins University, created a picture of the whole dynein-dynactin structure.

    “This work gives us critical insights into the regulation of the dynein motor and establishes a structural framework for understanding why defects in this system have been linked to diseases such as Huntington’s, Parkinson’s, and Alzheimer’s,” said Lander.

    The findings are reported in a Nature Structural & Molecular Biology advance online publication on March 9, 2015.

    Unprecedented Detail

    The proteins dynein and dynactin normally work together on microtubules for cellular activities such as cell division and intracellular transport of critical cargo such as mitochondria and mRNA. The complex also plays a key role in neuronal development and repair, and problems with the dynein-dynactin motor system have been found in brain diseases including Alzheimer’s, Parkinson’s and Huntington’s diseases, and amyotrophic lateral sclerosis (ALS). In addition, some viruses (including herpes, rabies and HIV) appear to hijack the dynein-dynactin transport system to get deep inside cells.

    “Understanding how dynein and dynactin interact and work, and how they actually look, is definitely going to have medical relevance,” said Research Associate Saikat Chowdhury, a member of the Lander lab who was first author of the study.

    To study the dynein-dynactin complex, Schroer’s laboratory first produced individual dynein and dynactin proteins, which are themselves complicated, with multiple subunits, but have been so highly conserved by evolution that they are found in almost identical form in organisms from yeast to mammals.

    Chowdhury and Lander then used electron microscopy (EM) and cutting-edge image-processing techniques to develop two-dimensional “snapshots” of dynein’s and dynactin’s basic structures. These structural data contained unprecedented detail and revealed subunits never observed before.

    Chowdhury and Lander next developed a novel strategy to purify and image dynein and dynactin in complex together on a microtubule—a railway-like structure, ubiquitous in cells, along which dynein-dynactin moves its cargoes.

    “This is the first snapshot of how the whole dynein-dynactin complex looks and how it is oriented on the microtubule,” Chowdhury said.

    Pushing the Limits

    The structural data clarify how dynein and dynactin fit together on a microtubule, how they recruit cargoes and how they manage to move those cargoes consistently in a single direction.

    Lander and Chowdhury now hope to build on the findings by producing a higher-resolution, three-dimensional image of the dynein-dynactin-microtubule complex, using an EM-related technique called electron tomography.

    “The EM facility at TSRI is the best place in the world to push the limits of imaging complicated molecular machines like these,” said Lander.

    The other co-author of the paper, Structural organization of the dynein–dynactin complex bound to microtubules, (doi:10.1038/nsmb.2996) was Stephanie A. Ketcham of the Schroer laboratory.

    The research was supported by the Damon Runyon Cancer Research Foundation (DFS-#07-13), the Pew Scholars program, the Searle Scholars program and the National Institutes of Health (DP2 EB020402-01, GM44589).

    See the full article here.

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    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

  • richardmitnick 6:35 am on March 8, 2015 Permalink | Reply
    Tags: , , Protein Studies, Proteomics   

    From ETH: “Personalising medicine with proteins” 

    ETH Zurich bloc

    ETH Zurich

    Fabio Bergamin

    Ruedi Aebersold, Professor of Systems Biology, is one of the world’s leading researchers in proteomics. In the last few years, he has developed the proteomics method together with a team of international researchers to such an extent that doctors and clinical researchers can now use this technique as a tool. In an interview with ETH News, the professor at ETH Zurich and the University of Zurich explains how information from proteins can advance what is commonly known as personalised medicine.

    “Proteins are the molecular players in cells, not genes,” says Ruedi Aebersold, professor at ETH and the University of Zurich. (Photo: Fabio Bergamin / ETH Zurich)

    ETH News: In future, medical researchers would like to better understand the individual differences among patients and the various manifestations of a disease in order to provide customised therapies. Until now, they have used mainly genomic differences; that is, mutations in the genetic material or DNA. Professor Aebersold, you are now going one step further and would like to entrench personalised medicine at the level of proteins. Why?

    Ruedi Aebersold: The molecular players that are the immediate cause of a disease in a body or a cell, are mostly proteins. Pathologists have long been able to measure specific proteins in tissue samples when they diagnose diseases; for example, a type of cancer. They can make these proteins visible with antibodies through the use of widely accepted, conventional methods. However, this identifies only a handful of proteins at a time. In recent years, we have developed a proteomics method by which we can precisely and simultaneously identify 2,000 proteins in a minute tissue sample.

    However, such methods to identify protein patterns are far more complex than existing genome analysis.
    It’s true that genetic mutations can now be identified quickly and relatively inexpensively. However, in cells the genetic information is processed; the proteins are at the end of the biological process chain and are more meaningful when describing a disease. By identifying thousands of proteins in tissue samples, we want to bridge the gap between genomics and diseases. Often a number of different genetic mutations lead to the same disease, or a disease is so complex with so many genetic puzzle pieces, of which we know very little about. Our proteomics method gives pathologists a modern tool with which they can classify diseased tissue far more precisely than before. We have developed proteomics to such an extent that we can deliver very precise and reproducible results in just one day.

    How do you achieve this?

    In order to identify proteins in a sample, we break them down into fragments called peptides. Using mass spectrometry, we can differentiate these peptides according to their mass and their ability to repel water.


    We assume that there are 10 to 100 million different peptides that may arise from the different proteins in the human body, which is far too many to analyse in a short time. Many previous proteomics methods therefore used a trick: according to the Las Vegas principle, they randomly chose approximately every 1000th peptide and analysed it. But this method has the big disadvantage the data generated are poorly reproducible because the same peptides are not chosen each time the same sample is analyzed. We, on the other hand, reduce the size of the data in a different way: we divide the peptides according to their mass and ability to repel water into about 30,000 groups and analyse them within an hour. Chance plays no part in our method and our technique is therefore both reproducible and fast.

    Over the last two years, you have refined the method and recently used it on patient tissue samples for the first time. To what effect?

    In our latest study, we measured the biochemical state of small biopsies, specifically kidney cancer biopsies, that we received from co-autors of the study, physicians at the Kantonspital St. Gallen. We were able to reproduce the pathologist’s findings at the protein level extremely well. Our technique enables us to create digital protein fingerprints of the samples. The advantage is that these fingerprints can be re-analysed at a later date, which means that researchers can use our data years later if they are interested in the function of a specific protein.

    Why is the speed of the method important?

    Proteomics allow us to make new discoveries best when we statistically analyse data from a large number of people, called a cohort. If a method is fast, then it has the capacity to examine large cohorts.

    You lead a research group of systems biologists. How have doctors at hospitals responded to your new method?

    We have received positive feedback from clinical researchers, and we anticipate that pathologists will soon be using the method to make clinical decisions. Proteomics used to have a bad reputation among physicians because it was comparatively expensive and complex, and it suffered from the Las Vegas syndrome, the poor reproducibility. We have now corrected this and are therefore convinced that our method has huge potential in clinics. We submitted our latest research to a medical journal for publication rather than a biological journal in the hope that it will make physicians and medical researchers more aware of the benefits of our technique. We are also pleased that our method not only works on our equipment; researchers have already adapted it for other equipment.

    How will you further develop the method?

    We are constantly working on increasing the number of measurable proteins. We also want to develop the method in such a way that we can measure older tissue samples that have been conserved in formalin. We could then analyse stored samples from patients about whom the subsequent course of disease and the chosen therapy is known. This would allow us to detect correlations between protein patterns and the course of the disease.

    Everyone is talking about personalised medicine these days, and new national research programmes are taking place in the UK and the US. What is the situation in Switzerland in respect to research on personalised medicine?

    We are very well positioned in Switzerland to explore complex diseases with a systems approach, in part thanks to the well-developed systems biology research in this country. And a centre of personalised medicine already exists through “Hochschulmedizin Zürich”. But more incentives are needed in order for physicians, researchers and engineers to work together more effectively. Similar to Barack Obama’s recent announcement in the US, it would be desirable to have a national research programme for personalised medicine in Switzerland, too. Scientists prepared a widely supported proposal to incorporate a such into the next legislative programme in 2017. At the end of 2016, the national research programme for systems biology, Systemsx.ch, will also come to an end as scheduled, and a personalised health programme could be built on it.


    About Ruedi Aebersold

    Ruedi Aebersold (60) is a pioneer in proteomics and systems biology. The journal Analytical Scientist described him in 2013 as the world’s second-most influential scientist in analytical sciences. After graduating from the University of Basel, Aebersold held positions at the California Institute of Technology and the University of Washington. He has been a professor of Systems Biology at ETH Zurich and University of Zurich since 2000/01.


    See the full article here.

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    ETH Zurich campus

    ETH Zurich is one of the leading international universities for technology and the natural sciences. It is well known for its excellent education, ground-breaking fundamental research and for implementing its results directly into practice.

    Founded in 1855, ETH Zurich today has more than 18,500 students from over 110 countries, including 4,000 doctoral students. To researchers, it offers an inspiring working environment, to students, a comprehensive education.

    Twenty-one Nobel Laureates have studied, taught or conducted research at ETH Zurich, underlining the excellent reputation of the university.

  • richardmitnick 2:01 pm on February 3, 2015 Permalink | Reply
    Tags: , Protein Studies,   

    From U Alberta: “Allergic drug reactions traced to single protein” 

    U Alberta bloc

    University of Alberta

    February 2, 2015
    Ross Neitz

    Research from UAlberta and Johns Hopkins University points to new strategy to reduce allergic responses to multiple medications.


    Every day in hospitals around the world, patients suffer painful allergic reactions to the medicines they are given. The reactions, known as pseudo-allergies, often cause patients to endure itchiness, swelling and rashes as an unwanted part of their treatment plan. The reactions can be so severe they may stop patients from taking their needed medications and sometimes can even prove fatal. It’s never been shown conclusively what triggers these allergic reactions—until now.

    “We are in the very early stages but we now understand how these pseudo-allergies are happening,” says Marianna Kulka, an adjunct assistant professor in the University of Alberta’s Department of Medical Microbiology and Immunology and project group leader with the National Institute for Nanotechnology. “This is a very large step forward in many ways.”

    In a study published in the December edition of the journal Nature, researchers from the U of A’s Faculty of Medicine & Dentistry and Johns Hopkins University identified a single protein as the root cause of allergic reactions to drugs and injections. They are now exploring ways to block the protein and reduce painful side effects caused by the reactions.

    “The drugs currently being used are to treat some very nasty diseases and they’re very effective at that. But side effects are a huge problem. If we can avoid these side effects by finding a way to block this problematic protein, we can really design drugs that are effective and safe,” says Kulka, a co-author on the study.

    In their findings the researchers focused on reactions triggered by medicines prescribed for a number of conditions that range from prostate cancer to diabetes to HIV. These reactions are different from the allergic reactions caused by food or experienced by hay fever sufferers.

    The scientists tested lab models with and without a single protein—named MRGPRB2—on their cells. The lab models without the protein did not suffer negative effects despite being given drugs known to provoke reactions.

    Benjamin McNeil, a post-doctoral fellow at Johns Hopkins University and study co-author, says, “It’s fortunate that all of the drugs turn out to trigger a single receptor—it makes that receptor an attractive drug target.”

    The researchers say if a new drug to block the protein receptor could be made, it would lessen the drug side-effects patients currently endure. Kulka believes with time, some painful reactions from medications can be avoided.

    “By understanding how they’re happening we can really help to avoid some of the pitfalls of designing drugs that cause the pseudo-allergies. We’ve got big plans in the future for trying to expand this [research] and better understand how this works.”

    Research funding was provided by the Canadian Institutes of Health Research and the National Institutes of Health.

    Other authors on the paper are Priyanka Pundir, a post-doctoral fellow with the U of A, and Sonya Meeker, Liang Han, Bradley J. Undem and Xinzhong Dong of Johns Hopkins University.

    See the full article here.

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    U Alberta Campus

    UAlberta’s daring and innovative spirit inspires faculty and students to advance knowledge through research, seek innovation in teaching and learning, and find new ways to serve the people of Alberta, the nation, and the world.

    The University of Alberta’s has had the vision to be one of the world’s great universities for the public good since its inception. This university is dedicated to the promise made by founding president Henry Marshall Tory that “… knowledge shall not be the concern of scholars alone. The uplifting of the whole people shall be its final goal.”

  • richardmitnick 8:02 am on January 24, 2015 Permalink | Reply
    Tags: , Protein Studies,   

    From UC Irvine: “Chemists find a way to unboil eggs” 

    UC Irvine bloc

    UC Irvine

    January 23, 2015
    Janet Wilson, UC Irvine


    UC Irvine and Australian chemists have figured out how to unboil egg whites — an innovation that could dramatically reduce costs for cancer treatments, food production and other segments of the $160 billion global biotechnology industry, according to findings published today in the journal ChemBioChem.

    “Yes, we have invented a way to unboil a hen egg,” said Gregory Weiss, UCI professor of chemistry and molecular biology & biochemistry. “In our paper, we describe a device for pulling apart tangled proteins and allowing them to refold. We start with egg whites boiled for 20 minutes at 90 degrees Celsius and return a key protein in the egg to working order.”

    Like many researchers, he has struggled to efficiently produce or recycle valuable molecular proteins that have a wide range of applications but which frequently “misfold” into structurally incorrect shapes when they are formed, rendering them useless.

    “It’s not so much that we’re interested in processing the eggs; that’s just demonstrating how powerful this process is,” Weiss said. “The real problem is there are lots of cases of gummy proteins that you spend way too much time scraping off your test tubes, and you want some means of recovering that material.”

    But older methods are expensive and time-consuming: The equivalent of dialysis at the molecular level must be done for about four days. “The new process takes minutes,” Weiss noted. “It speeds things up by a factor of thousands.”

    To re-create a clear protein known as lysozyme once an egg has been boiled, he and his colleagues add a urea substance that chews away at the whites, liquefying the solid material. That’s half the process; at the molecular level, protein bits are still balled up into unusable masses. The scientists then employ a vortex fluid device, a high-powered machine designed by professor Colin Raston’s laboratory at South Australia’s Flinders University. Shear stress within thin, microfluidic films is applied to those tiny pieces, forcing them back into untangled, proper form.

    “This method … could transform industrial and research production of proteins,” the researchers write in ChemBioChem.

    For example, pharmaceutical companies currently create cancer antibodies in expensive hamster ovary cells that do not often misfold proteins. The ability to quickly and cheaply re-form common proteins from yeast or E. coli bacteria could potentially streamline protein manufacturing and make cancer treatments more affordable. Industrial cheese makers, farmers and others who use recombinant proteins could also achieve more bang for their buck.

    UCI has filed for a patent on the work, and its Office of Technology Alliances is working with interested commercial partners.

    Besides Weiss and Raston, the paper’s authors are Tom Yuan, Joshua Smith, Stephan Kudlacek, Mariam Iftikhar, Tivoli Olsen, William Brown, Kaitlin Pugliese and Sameeran Kunche of UCI, as well as Callum Ormonde of the University of Western Australia. The research was supported by the National Institute of General Medical Sciences and the Australian Research Council.

    See the full article here.

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    UC Irvine Campus

    Since 1965, the University of California, Irvine has combined the strengths of a major research university with the bounty of an incomparable Southern California location. UCI’s unyielding commitment to rigorous academics, cutting-edge research, and leadership and character development makes the campus a driving force for innovation and discovery that serves our local, national and global communities in many ways.

    With more than 29,000 undergraduate and graduate students, 1,100 faculty and 9,400 staff, UCI is among the most dynamic campuses in the University of California system. Increasingly a first-choice campus for students, UCI ranks among the top 10 U.S. universities in the number of undergraduate applications and continues to admit freshmen with highly competitive academic profiles.

    UCI fosters the rigorous expansion and creation of knowledge through quality education. Graduates are equipped with the tools of analysis, expression and cultural understanding necessary for leadership in today’s world.

    Consistently ranked among the nation’s best universities – public and private – UCI excels in a broad range of fields, garnering national recognition for many schools, departments and programs. Times Higher Education ranked UCI No. 1 among universities in the U.S. under 50 years old. Three UCI researchers have won Nobel Prizes – two in chemistry and one in physics.

    The university is noted for its top-rated research and graduate programs, extensive commitment to undergraduate education, and growing number of professional schools and programs of academic and social significance. Recent additions include highly successful programs in public health, pharmaceutical sciences and nursing science; an expanding education school; and a law school already ranked among the nation’s top 10 for its scholarly impact.

  • richardmitnick 6:39 am on January 20, 2015 Permalink | Reply
    Tags: , Hunger, Protein Studies,   

    From UCSC: “Researchers find a novel signaling pathway involved in appetite control” 

    UC Santa Cruz

    UC Santa Cruz

    January 19, 2015
    Tim Stephens

    Agouti-related protein regulates feeding behavior, illustrated here in the Eastern chipmunk. (Photo by Ed Reschke)

    A new study has revealed important details of a molecular signaling system in the brain that is involved in the control of body weight and metabolism. The study, published January 19 in Nature, provides a new understanding of the melanocortin pathway and could lead to new treatments for obesity.

    Coauthor Glenn Millhauser, a distinguished professor of chemistry and biochemistry at UC Santa Cruz, said the findings are very exciting and have broad biomedical implications. “We are getting to the real molecular features of what’s controlling this important signaling system in the brain,” Millhauser said.

    The study, led by researchers at Vanderbilt University, focused on a receptor embedded in the membranes of nerve cells called the melanocortin-4 receptor, or MC4R. It belongs to a class of receptors known as G-protein coupled receptors (GPCRs), which typically act like on-off switches, signaling over short time frames, according to Roger Cone, who led the study at Vanderbilt.

    “This finding identifies a molecular mechanism for converting an on-off switch into a rheostat,” Cone said. “This could help explain slow, sustained biological processes that also are mediated by GPCRs, such as tanning or weight regain after dieting.”

    Millhauser’s lab has done extensive research on proteins that bind to the MC4R receptor, such as agouti-related protein (AgRP). AgRP is a potent appetite stimulant. Its role in regulating energy balance is to suppress metabolism and increase feeding when the body needs to put on weight and store energy, Millhauser said. His lab has developed modified versions of the AgRP protein that alter its activity. In the new study, the modified proteins from Millhauser’s lab helped researchers identify a previously unsuspected effect of AgRP.

    Millhauser’s previous studies have shown that a single dose of AgRP given to laboratory animals can stimulate daily food intake for up to 10 days. This observation didn’t fit with the traditional “on-off” signaling model for the receptor it binds to, MC4R. G-protein coupled receptors can only take so much stimulation before they shut down, and this phenomenon, called desensitization, often happens rapidly.

    Cone’s lab discovered a companion protein–a potassium channel in the membrane called Kir7.1–that couples to the MC4R receptor and acts independently from G-protein signaling. The researchers found that AgRP induces MC4R to open the potassium channel, which “hyperpolarizes” and inhibits neurons that are involved in blocking appetite.

    “Moreover, with modifications to AgRP discovered previously by our lab, we can increase or decrease this coupling of the receptor to the potassium channel,” Millhauser said. “These concepts could ultimately lead to new generations of therapeutics for treating metabolic disorders, including obesity, anorexia, and cachexia, the wasting condition that often occurs in cancer treatment.”

    Coauthor Rafael Palomino, a graduate student and NIH Fellow in Millhauser’s lab, did the protein synthesis and purification work for the study. The first author is Masoud Ghamari-Langroudi at Vanderbilt. Other contributors include Jerod Denton and Robert Matthews at Vanderbilt and Helen Cox at King’s College, London. This research was supported by the National Institutes of Health.

    See the full article here.

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    The University of California, Santa Cruz, opened in 1965 and grew, one college at a time, to its current (2008-09) enrollment of more than 16,000 students. Undergraduates pursue more than 60 majors supervised by divisional deans of humanities, physical & biological sciences, social sciences, and arts. Graduate students work toward graduate certificates, master’s degrees, or doctoral degrees in more than 30 academic fields under the supervision of the divisional and graduate deans. The dean of the Jack Baskin School of Engineering oversees the campus’s undergraduate and graduate engineering programs.

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