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  • richardmitnick 2:26 pm on February 2, 2017 Permalink | Reply
    Tags: , , , , Protein Studies   

    From Caltech: “Protein Chaperone Takes Its Job Seriously” 

    Caltech Logo



    Whitney Clavin
    (626) 395-1856

    Structural rendering of a ribosomal protein (yellow and red) bound to its chaperone (blue). By capturing an atomic-resolution snapshot of the pair of proteins interacting with each other, Ferdinand Huber, a graduate student in the lab of André Hoelz revealed that chaperones can protect their ribosomal proteins by tightly packaging them up. The red region illustrates where the dramatic shape alterations occur when the ribosomal protein is released from the chaperone during ribosome assembly. Credit: Huber and Hoelz/Caltech

    A diagram of the cell showing the process by which chaperone proteins (red) transport ribosomal proteins (beige) to the nucleus. The chaperones bind to the ribosomal proteins and usher them into the nucleus, while also protecting the proteins from liquidation machinery. Once a ribosomal protein reaches a growing ribosome (green and purple), the chaperone releases it. The nearly complete ribosome units exit the nucleus where they undergo final assembly. Credit: Huber and Hoelz/Caltech

    For proteins, this would be the equivalent of the red-carpet treatment: each protein belonging to the complex machinery of ribosomes—components of the cell that produce proteins—has its own chaperone to guide it to the right place at the right time and protect it from harm.

    In a new Caltech study, researchers are learning more about how ribosome chaperones work, showing that one particular chaperone binds to its protein client in a very specific, tight manner, almost like a glove fitting a hand. The researchers used X-ray crystallography to solve the atomic structure of the ribosomal protein bound to its chaperone.

    “Making ribosomes is a bit like baking a cake. The individual ingredients come in protective packaging that specifically fits their size and shape until they are unwrapped and blended into a batter,” says André Hoelz, professor of chemistry at Caltech, a Heritage Medical Research Institute (HMRI) Investigator, and Howard Hughes Medical Institute (HHMI) Faculty Scholar.” What we have done is figure out how the protective packaging fits one ribosomal protein, and how it comes unwrapped.” Hoelz is the principal investigator behind the study published February 2, 2017, in the journal Nature Communications. The finding has potential applications in the development of new cancer drugs designed specifically to disable ribosome assembly.

    In all cells, genetic information is stored as DNA and transcribed into mRNAs that code for proteins. Ribosomes translate the mRNAs into amino acids, linking them together into polypeptide chains that fold into proteins. More than a million ribosomes are produced per day in an animal cell.

    Building ribosomes is a formidable undertaking for the cell, involving about 80 proteins that make up the ribosome itself, strings of ribosomal RNA, and more than 200 additional proteins that guide and regulate the process. “Ribosome assembly is a dynamic process, where everything happens in a certain order. We are only now beginning to elucidate the many steps involved,” says Hoelz.

    To make matters more complex, the proteins making up a ribosome are first synthesized outside the nucleus of a cell, in the cytoplasm, before being transported into the nucleus where the initial stages of ribosome assembly take place.

    Chaperone proteins help transport ribosomal proteins to the nucleus while also protecting them from being chopped up by a cell’s protein shredding machinery. The components that specifically aim this machinery at unprotected ribosomal proteins, recently identified by Raymond Deshaies, professor of biology at Caltech and an HHMI Investigator, ensures that equal numbers of the various ribosomal proteins are available for building the massive structure of a ribosome.

    Structural rendering of a chaperone called Acl4 bound to ribosomal protein L4

    Previously, Hoelz and his team, in collaboration with the laboratory of Ed Hurt at the University of Heidelberg, discovered that a ribosomal protein called L4 is bound by a chaperone called “Assembly chaperone of RpL4,” or Acl4. The chaperone ushers L4 through the nucleus, protecting it from harm, and delivers it to a developing ribosome at a precise time and location. In the new study, the team used X-ray crystallography, a process that involves exposing protein crystals to high-energy X-rays, to solve the structure of the bound pair. The technique was performed at Caltech’s Molecular Observatory beamline at the Stanford Synchrotron Radiation Lightsource.

    “This was not an easy structure to solve,” says Ferdinand Huber, a graduate student at Caltech in the Hoelz lab and first author of the new study. “Solving the structure was incredibly exciting because you could see with your eyes, for the very first time, how the chaperone embraces the ribosomal protein to protect it.”

    Hoelz says that the structure was a surprise because it was not known previously that chaperones hold on to their ribosomal proteins so tightly. He says they want to study other chaperones in the future to see if they function in a similar fashion to tightly guard ribosomal proteins. The results may lead to the development of new drugs for cancer therapy by preventing cancer cells from supplying the large numbers of ribosomes required for tumor growth.

    The study, called “Molecular Basis for Protection of Ribosomal Protein L4 from Cellular Degradation,” was funded by a PhD fellowship of the Boehringer Ingelheim Fonds, a Faculty Scholar Award of the Howard Hughes Medical Research Institute, a Heritage Medical Research Institute Principal Investigatorship, a Kimmel Scholar Award of the Sidney Kimmel Foundation for Cancer Research, a Teacher-Scholar Award of the Camille & Henry Dreyfus Foundation, and Caltech startup funds.

    See the full article here .

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    The California Institute of Technology (commonly referred to as Caltech) is a private research university located in Pasadena, California, United States. Caltech has six academic divisions with strong emphases on science and engineering. Its 124-acre (50 ha) primary campus is located approximately 11 mi (18 km) northeast of downtown Los Angeles. “The mission of the California Institute of Technology is to expand human knowledge and benefit society through research integrated with education. We investigate the most challenging, fundamental problems in science and technology in a singularly collegial, interdisciplinary atmosphere, while educating outstanding students to become creative members of society.”
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  • richardmitnick 12:56 pm on February 2, 2017 Permalink | Reply
    Tags: , IRE1 inhibitor, , , Protein Studies, The unfolded protein response or UPR — has been implicated in a number of diseases,   

    From UCSB: “Origami of the Cell” 

    UC Santa Barbara Name bloc
    UC Santa Barbara

    January 30, 2017
    Julie Cohen

    These images show a reduction in the number of macrophages infiltrating atherosclerotic plaques (in green) in animals treated with the IRE1 inhibitor.
    Photo Credit: Courtesy IMAGE

    This shows a reduction in atherosclerotic lesions in the aorta of mice (in red) when treated with the IRE1 inhibitor.
    Photo Credit: Courtesy IMAGE

    In the ancient Japanese art of origami, paper must be folded precisely and following a specific order to create the desired result — say, a crane or lotus flower. It’s a complex pursuit that requires keen attention to detail and utmost accuracy.

    An equally precise biological process in living cells gives rise to proteins, the large biomolecules essential for life.

    Proteins begin life as long strings of amino acids that must fold into the three-dimensional shape prescribed for their particular biological function. When proteins don’t fold as expected — think badly misshapen crane — the cells activate stress responses meant to mitigate the problem. But severe or prolonged stress produces an acute response: Cell death is triggered to protect the organism.

    Sustained activation of one such reaction — the unfolded protein response, or UPR — has been implicated in a number of diseases. Seeking to illuminate a piece of this biological puzzle, an international team of scientists, including UC Santa Barbara cell biologist Diego Acosta-Alvear, examined the role of a central UPR component, a stress sensor protein called IRE1 (inositol-requiring enzyme 1), in atherosclerosis.

    The researchers found that blocking IRE1 with a small molecule prevented the progression of atherosclerosis in mice. The findings appear in the Proceedings of the National Academy of Sciences.

    “A healthy cell has one type of stress response network wiring and it’s likely that a diseased cell accommodates that wiring to survive,” said Acosta-Alvear, an assistant professor in UCSB’s Department of Molecular, Cellular and Developmental Biology. “Stress response networks control the life vs. death decision in cells, and since a diseased cell is nowhere near its comfort zone, rewiring its stress responses allows it to avoid or delay cell death even when conditions are adverse. That’s what we wanted to understand: how a diseased cell does that and why it happens.”

    The UPR is triggered when the normal functions of the endoplasmic reticulum — the cell’s largest organelle in charge of making and folding proteins — are compromised. Though the UPR usually promotes healthy endoplasmic reticulum function, sustained UPR activation sometimes results in diseases such as atherosclerosis, the deposition of fatty plaques on artery walls, among other conditions. Understanding what happens with the UPR in disease is key to illuminating the normal operation of this essential pathway — and to providing insights into the development of targeted therapies.

    Endoplasmic reticulum stress is triggered not only by protein-folding problems, but also by fatty acids, explained Acosta-Alvear. Fat-induced stress and metabolic overload of the endoplasmic reticulum can alter its function, triggering chronic inflammation, which plays an important role in the development of atherosclerosis.

    In this research, the scientists disturbed endoplasmic reticulum function by introducing saturated fatty acids into cells to induce lipotoxic stress. This in turn activated the UPR and IRE1.

    Active IRE1 relays the protein-folding stress information to the cell nucleus by controlling the production of a very potent transcription activator, XBP1 (X-box binding protein-1). Transcription activators are proteins involved in the process of converting, or transcribing, DNA into RNA.

    The investigators’ analyses demonstrated that XBP1 was responsible for turning on pro-atherogenic genes. They then treated mice with a compound that blocked IRE1.

    “The end result was that if the transcription factor was not produced, the pro-atherogenic genes were not turned on, which mitigated the progression of the disease,” Acosta-Alvear said. “This research is a proof-of-concept study showing that blocking this single critical enzyme delivers a desirable therapeutic benefit. It’s a first step in mechanistically understanding how cellular stress responses are wired in specific contexts.”

    See the full article here .

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    UC Santa Barbara Seal
    The University of California, Santa Barbara (commonly referred to as UC Santa Barbara or UCSB) is a public research university and one of the 10 general campuses of the University of California system. Founded in 1891 as an independent teachers’ college, UCSB joined the University of California system in 1944 and is the third-oldest general-education campus in the system. The university is a comprehensive doctoral university and is organized into five colleges offering 87 undergraduate degrees and 55 graduate degrees. In 2012, UCSB was ranked 41st among “National Universities” and 10th among public universities by U.S. News & World Report. UCSB houses twelve national research centers, including the renowned Kavli Institute for Theoretical Physics.

  • richardmitnick 2:49 pm on January 31, 2017 Permalink | Reply
    Tags: Protein Studies,   

    From Scripps: “New Method Could Turbocharge Drug Discovery, Protein Research” 

    Scripps Research Institute

    January 30, 2017
    Mo writer credit

    A team led by scientists at The Scripps Research Institute (TSRI) has developed a versatile new method that should enhance the discovery of new drugs and the study of proteins.

    The new method enables researchers to quickly find small molecules that bind to hundreds of thousands of proteins in their native cellular environment. Such molecules, called ligands, can be developed into important tools for studying how proteins work in cells, which may lead to the development of new drugs. The method can be used even without prior knowledge of protein targets to discover ligand molecules that disrupt a biological process of interest—and to quickly identify the proteins to which they bind.

    “This ,” said co-lead author Christopher G. Parker, a research associate in the laboratory of TSRI Professor Benjamin F. Cravatt, chairman of the Department of Chemical Biology.

    This research was published ahead of print recently in the journal Cell.

    Authors of the new study included (left to right) TSRI’s Andrea Galmozzi, Christopher Parker, Benjamin Cravatt and Enrique Saez. (Photo by Madeline McCurry-Schmidt.)

    Finding New Partners for Un-targetable Proteins

    About 25,000 proteins are encoded in the human genome, but public databases list known ligands for only about 10 percent of them. Biologists have long sought better tools for exploring this terra incognita.

    The new method involves the development of a set of small, but structurally varied, candidate ligand molecules known as “fragments.” Each candidate ligand is modified with a special chemical compound so that, when it binds with moderate affinity to a protein partner, it can be made to stick permanently to that partner by a brief exposure to UV light. A further modification provides a molecular handle by which scientists can grab and isolate these ligand-protein pairs for analysis.

    For an initial demonstration, the team assembled a small “library” of candidate ligands whose structural features include many that are found in existing drugs. By applying just 11 of them to human cells, the researchers identified more than 2,000 distinct proteins that had bound to one or more of the ligands.

    These ligand-bound proteins include many from categories—such as transcription factors—that previously had been considered “un-ligandable” and therefore un-targetable with drugs. In fact, only 17 percent of these proteins have known ligands, according to the widely used DrugBank database.

    The researchers used further methods to identify, for many ligand-protein interactions, the site on the protein where the coupling occurred.

    The candidate ligands initially used to screen for protein binding partners are generally too small to bind to their partners tightly enough to disrupt their functions in cells. But the team showed that, in multiple cases, that these initial small (“fragment”) ligands could be developed into larger, more complex molecules that display higher-affinity interactions and disrupt their protein partner’s functions.

    A New Type of Functional Screen

    For a final demonstration, collaborating chemists at Bristol-Myers Squibb helped create a library of several hundred slightly more complex candidate ligands. With TSRI colleagues Associate Professor Enrique Saez and co-first author Research Associate Andrea Galmozzi, the team then tested these ligands to find any that could promote the maturation of fat cells (adipocytes)—a process that in principle can alleviate the insulin resistance that leads to type 2 diabetes.

    Traditional functional screens of this type do not pinpoint the proteins or other molecules through which the effect on the cell occurs. But with this new discovery method, the researchers quickly found not only a ligand that strongly promotes adipocyte maturation but also its binding partner, PGRMC2, a protein about which little was known.

    “We found a new ‘druggable’ pathway, and we also seem to have uncovered some new biology—despite the fact that adipocyte maturation and other diabetes-related pathways have been studied a lot already,” Parker said.

    “With this method, we look forward to exploring much more thoroughly the druggability of human proteins and accelerating investigations of protein biology,” Cravatt added.

    In addition to Parker, Cravatt, Saez and Galmozzim authors of the study, “Ligand and Target Discovery by Fragment-Based Screening in Human Cells,” included TSRI’s Yujia Wang, Kenji Sasaki, Christopher Joslyn and Arthur S. Kim; Bruno Correia of Ecole Polytechnique Federal in Lausanne, Switzerland; and Cullen Cavallaro, Michael Lawrence and Stephen Johnson of Bristol-Myers Squibb.

    The work was supported by grants from the National Institutes of Health (DK099810; CA132630; 1S10OD16357), an American Cancer Society Postdoctoral Fellowship and a fellowship from the American Heart Association.

    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 2:48 pm on January 30, 2017 Permalink | Reply
    Tags: , , , Dr. Miriam Eisenstein, GSK-3, Modeling of molecules on the computer, Protein Studies, ,   

    From Weizmann: Women in STEM – “Staff Scientist: Dr. Miriam Eisenstein” 

    Weizmann Institute of Science logo

    Weizmann Institute of Science

    No writer credit found

    Name: Dr. Miriam Eisenstein
    Department: Chemical Research Support

    “The modeling of molecules on the computer,” says Dr. Miriam Eisenstein, Head of the Macromolecular Modeling Unit of the Weizmann Institute of Science’s Chemical Research Support Department, “is sometimes the only way to understand exactly how such complex molecules as proteins interact.”

    Eisenstein was one of the first to develop molecular docking methods while working with Prof. Ephraim Katzir – over two decades ago – and she has worked in collaboration with many groups at the Weizmann Institute.

    But even with all her experience, protein interactions can still surprise her. This was the case in a recent collaboration with the lab group of Prof. Hagit Eldar-Finkelman of Tel Aviv University, in research that was hailed as a promising new direction for finding treatments for Alzheimer’s disease. Eldar-Finkelman and her group were investigating an enzyme known as GSK-3, which affects the activity of various proteins by clipping a particular type of chemical tag, known as a phosphate group, onto them. GSK-3 thus performs quite a few crucial functions in the body, but it can also become overactive, and this extra activity has been implicated in a number of diseases, including diabetes and Alzheimer’s.

    The Tel Aviv group, explains Eisenstein, was exploring a new way of blocking, or at least damping down, the activity of this enzyme. GSK-3 uses ATP — a small, phosphate-containing molecule — in the chemical tagging process, transferring one of the ATP phosphate groups to a substrate. The ATP binding site on the enzyme is often targeted with ATP-like drug compounds that by themselves binding prevent the ATP from binding, thus blocking the enzyme’s activity. But such compounds are not discriminating enough, often blocking related enzymes in the process, which is an undesired side effect. This is why Eldar-Finkelman and her team looked for molecules that would compete with the substrate and occupy its binding cavity, so that the enzyme’s normal substrates cannot attach to GSK-3 and clip onto the phosphate groups.

    After identifying one molecule – a short piece of protein, or peptide – that substituted for GSK-3’s substrates in experiments, Eldar-Finkelman turned to Eisenstein to design peptides that would be better at competing with the substrate. At first Eisenstein computed model structures of the enzyme with an attached protein substrate and the enzyme with an attached peptide; she then characterized the way in which the enzyme binds either the substrate or the competing peptide. The model structures pinpointed the contacts, and these were verified experimentally by Eldar-Finkelman.

    This led to the next phase, a collaborative effort to introduce alterations to the peptide so as to improve its binding capabilities. One of the new peptides was predicted by Eisenstein to be a good substrate, and Eldar-Finkelman’s experiments showed that it indeed was. Once chemically tagged, the new peptide proved to be excellent at binding to GSK-3 – many times better than the original – and this was the surprise, because normally, once they are tagged, such substrates are repelled from the substrate-binding cavity and end up dissociating from the enzyme. Molecular modeling explained what was happening. After initially binding as a substrate and attaining a phosphate group, the peptide slid within the substrate-binding cavity, changing its conformation in the process, and attached tightly to a position normally occupied by the protein substrate.

    Experiments in Eldar-Finkelman’s group showed that this peptide is also active in vivo and, moreover, was able to reduce the symptoms of an Alzheimer-like condition in mice. The results of this research appeared in Science Signaling.

    “This experiment is a great example of the synergy between biologists and computer modelers,” says Eisenstein. “Hagit understands the function of this enzyme in the body, and she had this great insight on a possible way to control its actions. I am interested in the way that two proteins fit together and influence one another at the molecular and atomic levels, so I can provide the complementary insight.”

    “Molecular modeling is such a useful tool, it has enabled me to work with a great many groups and take part in a lot of interesting, exciting work, over the years,” she adds. “Computers have become much stronger in that time, but the basic, chemical principles of attraction and binding between complex molecules remain the same, and our work is as relevant as ever.”

    See the full article here .

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    Weizmann Institute Campus

    The Weizmann Institute of Science is one of the world’s leading multidisciplinary research institutions. Hundreds of scientists, laboratory technicians and research students working on its lushly landscaped campus embark daily on fascinating journeys into the unknown, seeking to improve our understanding of nature and our place within it.

    Guiding these scientists is the spirit of inquiry so characteristic of the human race. It is this spirit that propelled humans upward along the evolutionary ladder, helping them reach their utmost heights. It prompted humankind to pursue agriculture, learn to build lodgings, invent writing, harness electricity to power emerging technologies, observe distant galaxies, design drugs to combat various diseases, develop new materials and decipher the genetic code embedded in all the plants and animals on Earth.

    The quest to maintain this increasing momentum compels Weizmann Institute scientists to seek out places that have not yet been reached by the human mind. What awaits us in these places? No one has the answer to this question. But one thing is certain – the journey fired by curiosity will lead onward to a better future.

  • richardmitnick 8:50 am on January 24, 2017 Permalink | Reply
    Tags: , , Endoplasmic reticulum, Protein Studies, Snd2, SRP pathway,   

    From Weizman: “Outward-Bound Proteins Have a Third Way” 

    Weizmann Institute of Science logo

    Weizmann Institute of Science

    No writer credit found

    A newly discovered “shuttle” for proteins is a “safety net” for vital communication between cells.

    Snd2 was tagged with a green fluorescent protein, and the endoplasmic reticulum was marked with a red fluorescent protein. The overlap between the green and red microscopy signals indicates that the newly discovered Snd2 is a receptor on the endoplasmic reticulum membrane. No image credit.

    The cells in our bodies must constantly communicate with one another. For many, it is a matter of survival; for others, it is the way they keep our bodies healthy and functioning efficiently. Communications are carried out by proteins – both the numerous proteins that are situated on the cells’ outer membranes to receive the messages and the messengers themselves, which are secreted to the outside of the cell. For most of these proteins, getting to the outside of the cell involves passage through an organelle called the endoplasmic reticulum. This first entails getting across the membrane of this organelle, to which the proteins are targeted, with the help of a special “shuttle” that conducts them to a sort of “transit area,” checking them first to see if they have the proper “passports.”

    How many different shuttles are needed to move all these proteins – in effect, around 30% of all the proteins in each cell? Previous studies of the past few decades have identified two – sort of couriers, like FedEx or DHL for proteins. Now, a new study [Nature], conducted in the lab of Prof. Maya Schuldiner of the Institute’s Molecular Genetics Department, has uncovered a third shuttle, and raised the possibility that more might be awaiting discovery.

    (l-r) Naama Aviram and Prof. Maya Schuldiner describe a ‘safety net’ for communication proteins. No image credit.

    The study was led by research student Naama Aviram, in collaboration with the labs of Prof. Richard Zimmerman of Saarland University, Germany, Prof. Blanche Schwappach of Göttingen University, also inGermany, and Prof. Jonathan Weissman of the University of California, San Francisco. “The first pathway for transferring proteins into the endoplasmic reticulum was discovered in the 1980s,” says Schuldiner. “Scientists found that this shuttle, called SRP, identifies the protein to be transported by reading a tag that is a sort of ‘passport’.”

    But this finding was not the whole story: Although many proteins use the SRP pathway to get to the endoplasmic reticulum membrane, this shuttle system seemed to have trouble identifying other outward-bound proteins. The reason eventually became clear: SRP easily identifies the tag when it is situated at one end of the protein, but has a hard time with tags at the other end. “This suggested that there was another pathway to catch the proteins that SRP misses,” says Schuldiner. “We identified that pathway in 2008 and named it GET.”

    The “shuttles” that lead proteins to the endoplasmic reticulum: the two previously known SRP and GET pathways, together with the newly discovered SND pathway, each caters for proteins with a different position of their “passports”. No image credit.

    But even with two shuttle services, the scientists noted there were still proteins that were not easily recognized by the pathways. “These are proteins that, if they are not efficiently transported to the endoplasmic reticulum, the cell dies. So we undertook a search for yet another pathway,” says Aviram.

    The team began their experiments in yeast cells, whose basic functions are nearly identical to those of human cells, and then tested their results in human cells. To begin, the researchers identified proteins that need to pass through the endoplasmic reticulum transit area, but do not receive assistance from either known pathway.

    Then, using the advanced robotic system in Schuldiner’s lab, they systematically looked at the ability of a protein to reach the endoplasmic reticulum membrane in the absence of each gene in the yeast cell, finding three that appeared to be necessary to the process of transporting these particular “problematic” proteins. When these genes were missing, the researchers observed accumulations of protein within the cell – proteins that had not managed to reach their destination outside of it.

    The three genes, which the team called SND1, SND2 and SND3, work together; one on the ribosome (the cell’s protein-manufacturing complex) and the other two at the “gates” of the endoplasmic reticulum.

    Together with the Weissman lab in San Francisco, the scientists revealed that this third pathway is active when the “passport” is closer to the center of the protein – the region the other two pathways have a hard time reading. “The new pathway functions as a ‘safety net’ for crucial proteins that may need to catch the next shuttle, but have their tags in inconvenient places,” says Schuldiner.

    Together with the Zimmerman lab, the researchers then asked whether this was occurring in a similar way in human cells. The scientists silenced the human SND2 gene – which they found has been conserved throughout evolution – and showed that here, too, the passage into the endoplasmic reticulum was defective, suggesting that this third pathway is at work in human cells as it is in yeast.

    “Many diseases, for example diabetes, involve disruption to intercellular communications,” says Schuldiner. “And we don’t always know just where the message goes astray. Maybe, in the future, understanding this pathway might help us figure out how to treat disease and save lives.”

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

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    Weizmann Institute Campus

    The Weizmann Institute of Science is one of the world’s leading multidisciplinary research institutions. Hundreds of scientists, laboratory technicians and research students working on its lushly landscaped campus embark daily on fascinating journeys into the unknown, seeking to improve our understanding of nature and our place within it.

    Guiding these scientists is the spirit of inquiry so characteristic of the human race. It is this spirit that propelled humans upward along the evolutionary ladder, helping them reach their utmost heights. It prompted humankind to pursue agriculture, learn to build lodgings, invent writing, harness electricity to power emerging technologies, observe distant galaxies, design drugs to combat various diseases, develop new materials and decipher the genetic code embedded in all the plants and animals on Earth.

    The quest to maintain this increasing momentum compels Weizmann Institute scientists to seek out places that have not yet been reached by the human mind. What awaits us in these places? No one has the answer to this question. But one thing is certain – the journey fired by curiosity will lead onward to a better future.

  • richardmitnick 2:33 pm on January 23, 2017 Permalink | Reply
    Tags: , , , , Protein Studies, Stable versions of synthetic peptides, Tailor-made drug molecules   

    From ALCF: “A rising peptide: Supercomputing helps scientists come closer to tailoring drug molecules” 

    Argonne Lab
    News from Argonne National Laboratory

    ANL Cray Aurora supercomputer
    Cray Aurora supercomputer at the Argonne Leadership Computing Facility

    MIRA IBM Blue Gene Q supercomputer at the Argonne Leadership Computing Facility
    MIRA IBM Blue Gene Q supercomputer at the Argonne Leadership Computing Facility


    January 23, 2017
    Robert Grant

    An artificial peptide made from a mixture of natural L-amino acids (the right half of the molecule) and non-natural, mirror-image D-amino acids (the left half of the molecule), designed computationally using INCITE resources. This peptide is designed to fold into a stable structure with a topology not found in nature, featuring a canonical right-handed alpha-helix packing against a non-canonical left-handed alpha-helix. Since structure imparts function, the ability to design non-natural structures permits scientists to create exciting new functions never explored by natural proteins. This peptide was synthesized chemically, and its structure was solved by nuclear magnetic resonance spectroscopy to confirm that it does indeed adopt this fold. The peptide backbone is shown as a translucent gold ribbon, and amino acid side-chains are shown as dark sticks. The molecular surface is shown as a transparent outline. Credit: Vikram Mulligan, University of Washington

    A team of researchers led by biophysicists at the University of Washington have come one step closer to designing tailor-made drug molecules that are more precise and carry fewer side effects than most existing therapeutic compounds.

    With the help of the Mira supercomputer, located at the Argonne Leadership Computing Facility at the U.S. Department of Energy’s (DOE) Argonne National Laboratory, the scientists have successfully designed and verified stable versions of synthetic peptides, components that join together to form proteins.

    They published their work in a recent issue of Nature.

    The computational protocol, which was validated by assembling physical peptides in the chemistry lab and comparing them to the computer models, may one day enable drug developers to craft novel, therapeutic peptides that precisely target specific disease-causing molecules within the body. And the insights the researchers gleaned constitute a significant advance in the fundamental understanding of protein folding.

    “That you can design molecules from scratch that fold up into structures, some of which are quite unlike what you see in nature, demonstrates a pretty fundamental understanding of what goes on at the molecular level,” said David Baker, the University of Washington biophysicist who led the research. “That’s certainly one of the more exciting things about this work.”

    Baker Lab

    David Baker
    David Baker

    The majority of drugs that humans use to treat the variety of ailments we suffer are so-called “small molecules.” These tiny compounds easily pass through different body systems to target receptor proteins studded in the membranes of our cells.

    Most do their job well, but they come with a major drawback: “Most drugs in use right now are small molecules, which are very tiny and nonspecific. They bind to lots of different things, which produces lots of side effects,” said Vikram Mulligan, a postdoctoral researcher in Baker’s lab and coauthor on the paper.

    More complex protein drugs ameliorate this problem, but they less readily disperse throughout the body because the more bulky molecules have a harder time passing through blood vessels, the linings of the digestive tract and other barriers.

    And proteins, which are giant on the molecular scale, have several layers of structure that all overlap to make them less static and more dynamic, making predicting their binding behavior a tricky prospect.

    But between the extremes of small, but imprecise, molecules and floppy, but high-specificity proteins, there exists a middle ground – peptides. These short chains of amino acids, which normally link together to make complex proteins, can target specific receptors, diffuse easily throughout the body and also sustain a rigid structure.

    Some naturally-occurring peptides are already used as drugs, such as the immunosuppressant ciclosporin, but researchers could open up a world of pharmaceutical opportunity if they could design and synthesize peptides.

    That’s precisely what Baker and his team did, tweaking the Rosetta software package that they built for the design of protein structures to accommodate synthetic amino acids that do not exist in nature, in addition to the 20 natural amino acids.

    After designing the chemical building blocks of peptides, the researchers used the supercomputer Mira, with its 10 petaflops of processing power and more than 780,000 cores, to model scores of potential shapes, or conformations, that specific backbone sequences of amino acids might take.

    “We basically sample millions and millions of these conformations,” said Yuri Alexeev, a project specialist in computational science at the Argonne Leadership Computing Facility, which is a DOE Office of Science User Facility. “At the same time you also improve the energy functions,” which are measurements to describe the efficiency and stability of each possible folding arrangement.

    Though he was not a coauthor on the Nature paper, Alexeev helped Baker’s team scale up previous programs it had used to design proteins for modeling peptides on Mira.

    Executing so many calculations simultaneously would be virtually impossible without Mira’s computing power, according to Mulligan.

    “The big challenge with designing peptides that fold is that you have a chain of amino acids that can exist in an astronomical number of conformations,” he said.

    Baker and his colleagues had tasked Mira with modeling millions of potential peptide conformations before, but this study stands out for two reasons.

    First, the researchers arrived at a handful of peptides with specific conformations that the computations predicted would be stable.

    Second, when Baker’s lab created seven of these peptides in their physical wet lab, the reality of the peptides’ conformations and stability corresponded remarkably well with the computer models.

    “At best, what comes out of a computer is a prediction, and at worst what comes out of a computer is a fantasy. So we never really consider it a result until we’ve actually made the molecule in the wet lab and confirmed that it actually has the structure that we designed it to have,” said Mulligan.

    “That’s exactly what we did in this paper,” he said. “We made a panel of these peptides that were designed to fold into very specific shapes, diverse shapes, and we experimentally confirmed that all of them folded into the shapes that we designed.”

    While this experiment sought to create totally new peptides in stable conformations as a proof of concept, Mulligan says that the Baker lab is now moving on to design functional peptides with specific targets in mind.

    Further research may bring the team closer to a protocol that could actually be used to design peptide drugs that target a specific receptor, such as those that make viruses like Ebola or HIV susceptible to attack.

    Computer time was awarded by the Innovative and Novel Computational Impact on Theory and Experiment (INCITE) program; the project also used resources of the Environmental Molecular Sciences Laboratory, a DOE Office of Science User Facility at Pacific Northwest National Laboratory.

    See the full article here .

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    Argonne National Laboratory seeks solutions to pressing national problems in science and technology. The nation’s first national laboratory, Argonne conducts leading-edge basic and applied scientific research in virtually every scientific discipline. Argonne researchers work closely with researchers from hundreds of companies, universities, and federal, state and municipal agencies to help them solve their specific problems, advance America’s scientific leadership and prepare the nation for a better future. With employees from more than 60 nations, Argonne is managed by UChicago Argonne, LLC for the U.S. Department of Energy’s Office of Science. For more visit http://www.anl.gov.

    About ALCF

    The Argonne Leadership Computing Facility’s (ALCF) mission is to accelerate major scientific discoveries and engineering breakthroughs for humanity by designing and providing world-leading computing facilities in partnership with the computational science community.

    We help researchers solve some of the world’s largest and most complex problems with our unique combination of supercomputing resources and expertise.

    ALCF projects cover many scientific disciplines, ranging from chemistry and biology to physics and materials science. Examples include modeling and simulation efforts to:

    Discover new materials for batteries
    Predict the impacts of global climate change
    Unravel the origins of the universe
    Develop renewable energy technologies

    Argonne is managed by UChicago Argonne, LLC for the U.S. Department of Energy’s Office of Science

    Argonne Lab Campus

  • richardmitnick 2:55 pm on January 7, 2017 Permalink | Reply
    Tags: , , Protein Studies, ,   

    From Uncovering Genome Mysteries at WCG: “Big Data and Big Plans: Next Steps for Uncovering Genome Mysteries” 

    New WCG Logo


    World Community Grid (WCG)

    15 Dec 2016 [Under what rock have you been hiding?]
    Wim Degrave, Ph.D.
    Laboratório de Genômica Funcional e Bioinformática Instituto Oswaldo Cruz – Fiocruz

    World Community Grid’s role in the Uncovering Genome Mysteries project has ended, but the research team’s work continues as they analyze the results of the calculations and prepare to apply the data to medical, agricultural, and other real-world applications.

    A diver collects samples from seawood off the coast of Australia. Uncovering Genome Mysteries analyzed protein sequences from a wide variety of life forms in many environments such as the ocean.


    The Uncovering Genome Mysteries project began on World Community Grid in November 2014, with the aim of analyzing protein sequences to help understand how organisms function and interact with each other and the environment. The project began with 120 million predicted protein sequences from close to 150,000 organisms. These protein sequences and organisms represent a wide variety of known or uncharacterised life forms in our biosphere. They came from organisms in samples taken from a range of environments, including water and soil, as well as on and inside plants and animals. Additionally, 70 million sequences, derived from prospective analysis of genetic information from microbial marine ecosystems from Australia were added, with the objective to add to the identification of possible functionalities of these sequences. In July 2015, we added yet another 20 million newly predicted sequences of proteins.

    Thanks to the enthusiastic contributions of more than 76,000 World Community Grid volunteers, all of these protein sequences were analyzed in approximately 24 months.

    Uncovering Genome Mysteries has been a challenging and ambitious project. Analyzing all the predicted enzymes and other proteins encoded in the genetic information known thus far from of all the organisms and life forms from our biosphere is a large task. Due to the development of new sequencing technologies for fast and cheap determination of genetic code, additional basic information will become available at an accelerating rate, making it increasingly difficult [?]to perform such a complete comparative analysis in the future.

    Our daunting task of performing close to 100 quadrillion comparisons has now been completed. The resulting data is more than 30 terabytes of compressed information (more than 150 terabytes uncompressed), even though each comparison only resulted in a single line of numbers for only the very highest probability similarities between protein sequences.

    Results to Date and Plans for the Future

    So, what is next? The research team at Fiocruz has spent the last year designing and testing new algorithms to transform the output of the comparisons with distance calculations between the genomes of the organisms included. Scientific literature cites many different ways to do this, depending on the purpose of the analysis and the views on evolutionary biology.

    The results of the Uncovering Genome Mysteries can be summarized as follows:

    More complete and precise information is now available on the structure and function of proteins encoded by living organisms in our biosphere. More proteins are being studied and experimented with each day in the thousands of laboratories around the world, and by using results from the comparison performed through the project, functional parallels can be drawn for proteins that show structural similarity between organisms. This is particularly valuable when predicted protein fragments are compared from uncharacterised organisms, for example in environmental and ecology studies, such as those originated from the laboratory of co-investigator Dr. Torsten Thomas, and his team from the Centre for Marine Bio-Innovation & the School of Biological, Earth and Environmental Sciences at the University of New South Wales, Sydney, Australia. The resulting database with these functional annotations will be made publicly available as the next version of our protein comparison database, ProteinWorldDB, in the coming months.

    Through comparison, new protein functions are discovered that can have medical, agricultural, technological or industrial applications. These can be as new biopharmaceuticals, bioinsecticides, biodegradation of waste, or enzymes for production of chemicals, but especially when part of new biochemical pathways in cells, that help laboratories to develop new green chemistry or energy production, or biosynthesis and transformation of new drugs. This also adds to the growing knowledge of biotechnology and synthetic biology.

    The group at Fiocruz has developed new ways to compare genomes from different organisms. Traditionally, such analyses consider what is conserved between genomes, resulting in distance calculations that are used for phylogenetic studies and the estimation of evolutionary relationships between organisms. However, we feel that this is only part of the picture, and the Fiocruz team designed a new algorithm that also takes differences into account. This was coupled to a new visualization method for such comparisons, resulting in a markedly faster way to add new data to the picture. We hope that this method will enable us to keep track of data from new organisms that becomes available, adding results to the growing ProteinWorld DB database.

    Thank you to all World Community Grid volunteers who supported this project, and we plan to keep in touch as we have further news about our ongoing research.

    See the full article here.

    Please help promote STEM in your local schools.
    STEM Icon

    Stem Education Coalition

    World Community Grid (WCG) brings people together from across the globe to create the largest non-profit computing grid benefiting humanity. It does this by pooling surplus computer processing power. We believe that innovation combined with visionary scientific research and large-scale volunteerism can help make the planet smarter. Our success depends on like-minded individuals – like you.”
    WCG projects run on BOINC software from UC Berkeley.

    BOINC is a leader in the field(s) of Distributed Computing, Grid Computing and Citizen Cyberscience.BOINC is more properly the Berkeley Open Infrastructure for Network Computing.

    BOINC WallPaper



    “Download and install secure, free software that captures your computer’s spare power when it is on, but idle. You will then be a World Community Grid volunteer. It’s that simple!” You can download the software at either WCG or BOINC.

    Please visit the project pages-

    FightAIDS@home Phase II

    FAAH Phase II

    Rutgers Open Zika

    Help Stop TB
    WCG Help Stop TB
    Outsmart Ebola together

    Outsmart Ebola Together

    Mapping Cancer Markers

    Uncovering Genome Mysteries
    Uncovering Genome Mysteries

    Say No to Schistosoma

    GO Fight Against Malaria

    Drug Search for Leishmaniasis

    Computing for Clean Water

    The Clean Energy Project

    Discovering Dengue Drugs – Together

    Help Cure Muscular Dystrophy

    Help Fight Childhood Cancer

    Help Conquer Cancer

    Human Proteome Folding


    World Community Grid is a social initiative of IBM Corporation
    IBM Corporation

    IBM – Smarter Planet

  • richardmitnick 11:20 am on December 4, 2016 Permalink | Reply
    Tags: , , , Protein Studies,   

    From Weizmann: “When Cells Are Fit” 

    Weizmann Institute of Science logo

    Weizmann Institute of Science

    07.11.2016 [I guess this has just ben in hiding.]
    No writer credit found

    How do the expression levels of numerous proteins affect a cell’s fitness?

    Tracking protein activity levels in a cell is essential to the study of such diseases as cancer which, alongside changes in the genes, involves changes in the activity levels of numerous proteins. However, deducing function, fitness and cellular well-being from the growing number of protein level measurements is still a major challenge. For example, is a two-fold – or 100-fold – range in activity for a particular protein tolerable over the population, or does it herald differences in the way that the cells carry out their tasks? Charting this connection could transform the way we diagnose, monitor and treat patients.

    (l-r) Maya Lotan-Pompan, Leeat Yankielowicz Keren and Prof. Eran Segal can now look at multiple protein expression levels at once

    “Most experiments examining ranging protein activity levels have, until now, focused on single proteins. What we did was to develop a way to systematically vary activity levels for hundreds of different proteins – all in a single experiment – and accurately measure how this affects the function of the cells,” says Leeat Yankielowicz Keren, a research student in the group of Prof. Eran Segal of the Computer Science and Applied Mathematics, and Molecular Cell Biology Departments at the Weizmann Institute of Science.

    The basic idea of the experiment in Segal’s lab was to create a competition in which common bakers’ yeast cells are pitted against one another. Each cell was nearly identical to its neighbors, except for a tweak to the activity level of one of its proteins. Thousands of these genetically engineered yeast cells were grown together in lab dishes; the “winners” were those in which expression levels boosted their fitness, basically enabling the yeast to eat more, grow and divide faster.

    Segal and his group developed a high-throughput genetic engineering technique that enabled them to manipulate the activity levels of different protein levels within thousands of cells simultaneously, precisely controlling, for each, the amounts of one particular protein. With 130 different activity levels – the highest 500 times the lowest – attached to 81 different protein-encoding sequences, the researchers created something like 10,000 different variations on the basic yeast cell, assigning each a “barcode” for convenient identification. With a combination of DNA sequencing techniques and an algorithm they created to reconstruct the growth rates of the various yeast cells, the team was then able to accurately map the connections between protein levels and the fitness of the cell.

    The competition took place in two different “arenas.” In one, the yeast were fed the glucose sugar they prefer; in the second, they were fed a different kind of sugar, galactose. The team found that when the competition took place on the kind of sugar it prefers, the original, untouched version of the yeast cell was the overall winner – testimony to the efficiency of evolution. But on the second kind of sugar, others came out on top. These results showed that around 20% of the yeast’s natural protein activity levels are too low or too high for growing on this sugar. This could be relevant to biotechnology: The second sugar is cheaply and abundantly found in seaweed, and the yeast break it down into ethanol, which can be burned in place of fossil fuels. The study suggests that genetically engineering yeast to alter some of these protein levels could significantly increase the efficiency of this process.

    Mapping all the activity patterns together enabled the group to begin to see patterns in the chaos. Similar activity patterns, for example, pointed to proteins that work together. Further analysis even revealed the “math” that cells use to produce these proteins in the right ratios, for example, for the construction of complexes that require exact proportions of their various proteins.

    Some of the proteins appeared to operate in a very narrow range – levels even a bit below or above this range drastically affected the fitness of the yeast. Others seemed to be much more flexible – a little or a lot did not affect the cell’s fitness, at least for the particular growing conditions. Those showing the larger ranges in the fitness competition turned out to be proteins that ordinarily vary widely from cell to cell in the natural yeast population. These findings suggest that understanding this flexibility can shed light on how activity levels are selected in evolution.

    Gene fitness profiles are different when yeast are grown on a sugar they normally prefer less

    For Segal and his team, the future goal is to create similar maps for protein activity levels in human cells. Such maps could form the basis of future diagnostic techniques that would be much more refined and precise than those of today, based on blood tests that already exist or can easily be developed. They might reveal the effects of diet or medications; and they could provide early diagnosis of cancer. Keren: “We want to eventually create a ‘chart’ that doctors can use to know which protein levels to check, and what levels should, ideally, be appearing in order to prevent disease.”

    Also participating in this study were Maya Lotan-Pompan and Dr. Adina Weinberger of Prof. Segal’s group, Dr. Jean Hausser and Prof. Uri Alon of the department of Molecular Cell Biology and Prof. Ron Milo of the department of Plant and Environmental Sciences.

    Science paper:
    Massively Parallel Interrogation of the Effects of Gene Expression Levels on Fitness, Cell

    See the full article here .

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    Weizmann Institute Campus

    The Weizmann Institute of Science is one of the world’s leading multidisciplinary research institutions. Hundreds of scientists, laboratory technicians and research students working on its lushly landscaped campus embark daily on fascinating journeys into the unknown, seeking to improve our understanding of nature and our place within it.

    Guiding these scientists is the spirit of inquiry so characteristic of the human race. It is this spirit that propelled humans upward along the evolutionary ladder, helping them reach their utmost heights. It prompted humankind to pursue agriculture, learn to build lodgings, invent writing, harness electricity to power emerging technologies, observe distant galaxies, design drugs to combat various diseases, develop new materials and decipher the genetic code embedded in all the plants and animals on Earth.

    The quest to maintain this increasing momentum compels Weizmann Institute scientists to seek out places that have not yet been reached by the human mind. What awaits us in these places? No one has the answer to this question. But one thing is certain – the journey fired by curiosity will lead onward to a better future.

  • richardmitnick 7:36 am on September 24, 2016 Permalink | Reply
    Tags: , , Protein Studies, Research at Princeton   

    From Research at Princeton: “New method identifies protein-protein interactions on basis of sequence alone (PNAS)” 

    Princeton University
    Princeton University

    September 23, 2016
    Catherine Zandonella, Office of the Dean for Research

    Researchers can now identify which proteins will interact just by looking at their sequences. Pictured are surface representations of a histidine kinase dimer (HK, top) and a response regulator (RR, bottom), two proteins that interact with each other to carry out cellular signaling functions. (Image based on work by Casino, et. al. credit: Bitbol et. al 2016/PNAS.)

    Genomic sequencing has provided an enormous amount of new information, but researchers haven’t always been able to use that data to understand living systems.

    Now a group of researchers has used mathematical analysis to figure out whether two proteins interact with each other, just by looking at their sequences and without having to train their computer model using any known examples. The research, which was published online today in the journal Proceedings of the National Academy of Sciences, is a significant step forward because protein-protein interactions underlie a multitude of biological processes, from how bacteria sense their surroundings to how enzymes turn our food into cellular energy.

    “We hadn’t dreamed we’d be able to address this,” said Ned Wingreen, Princeton University‘s Howard A. Prior Professor in the Life Sciences, and a professor of molecular biology and the Lewis-Sigler Institute for Integrative Genomics, and a senior co-author of the study with Lucy Colwell of the University of Cambridge. “We can now figure out which protein families interact with which other protein families, just by looking at their sequences,” he said.

    Although researchers have been able to use genomic analysis to obtain the sequences of amino acids that make up proteins, until now there has been no way to use those sequences to accurately predict protein-protein interactions. The main roadblock was that each cell can contain many similar copies of the same protein, called paralogs, and it wasn’t possible to predict which paralog from one protein family would interact with which paralog from another protein family. Instead, scientists have had to conduct extensive laboratory experiments involving sorting through protein paralogs one by one to see which ones stick.

    In the current paper, the researchers use a mathematical procedure, or algorithm, to examine the possible interactions among paralogs and identify pairs of proteins that interact. The method was able to correctly predict 93% of the protein-protein paralog pairs that were present in a dataset of more than 20,000 known paired protein sequences, without being first provided any examples of correct pairs.

    Interactions between proteins happen when two proteins come into physical contact and stick together via weak bonds. They may do this to form part of a larger piece of machinery used in cellular metabolism. Or two proteins might interact to pass a signal from the exterior of the cell to the DNA, to enable a bacterial organism to react to its environment.

    When two proteins come together, some amino acids on one chain stick to the amino acids on the other chain. Each site on the chain contains one of 20 possible amino acids, yielding a very large number of possible amino-acid pairings. But not all such pairings are equally probable, because proteins that interact tend to evolve together over time, causing their sequences to be correlated.

    The algorithm takes advantage of this correlation. It starts with two protein families, each with multiple paralogs in any given organism. The algorithm then pairs protein paralogs randomly within each organism and asks, do particular pairs of amino acids, one on each of the proteins, occur much more or less frequently than chance? Then using this information it asks, given an amino acid in a particular location on the first protein, which amino acids are especially favored at a particular location on the second protein, a technique known as direct coupling analysis. The algorithm in turn uses this information to calculate the strengths of interactions, or “interaction energies,” for all possible protein paralog pairs, and ranks them. It eliminates the unlikely pairings and then runs again using only the top most likely protein pairs.

    The most challenging part of identifying protein-protein pairs arises from the fact that proteins fold and kink into complicated shapes that bring amino acids in proximity to others that are not close by in sequence, and that amino-acids may be correlated with each other via chains of interactions, not just when they are neighbors in 3D. The direct coupling analysis works surprisingly well at finding the true underlying couplings that occur between neighbors.

    The work on the algorithm was initiated by Wingreen and Robert Dwyer, who earned his Ph.D. in the Department of Molecular Biology at Princeton in 2014, and was continued by first author Anne-Florence Bitbol, who was a postdoctoral researcher in the Lewis-Sigler Institute for Integrative Genomics and the Department of Physics at Princeton and is now a CNRS researcher at Universite Pierre et Marie Curie – Paris 6. Bitbol was advised by Wingreen and Colwell, an expert in this kind of analysis who joined the collaboration while a member at the Institute for Advanced Study in Princeton, NJ, and is now a lecturer in chemistry at the University of Cambridge.

    The researchers thought that the algorithm would only work accurately if it first “learned” what makes a good protein-protein pair by studying ones discovered in experiments. This required that the researchers give the algorithm some known protein pairs, or “gold standards,” against which to compare new sequences. The team used two well-studied families of proteins, histidine kinases and response regulators, which interact as part of a signaling system in bacteria.

    But known examples are often scarce, and there are tens of millions of undiscovered protein-protein interactions in cells. So the team decided to see if they could reduce the amount of training they gave the algorithm. They gradually lowered the number of known histidine kinase-response regulator pairs that they fed into the algorithm, and were surprised to find that the algorithm continued to work. Finally, they ran the algorithm without giving it any such training pairs, and it still predicted new pairs with 93 percent accuracy.

    “The fact that we didn’t need a gold standard was a big surprise,” Wingreen said.

    Upon further exploration, Wingreen and colleagues figured out that their algorithm’s good performance was due to the fact that true protein-protein interactions are relatively rare. There are many pairings that simply don’t work, and the algorithm quickly learned not to include them in future attempts. In other words, there is only a small number of distinctive ways that protein-protein interactions can happen, and a vast number of ways that they cannot happen. Moreover, the few successful pairings were found to repeat with little variation across many organisms. This it turns out, makes it relatively easy for the algorithm to reliably sort interactions from non-interactions.

    Wingreen compared this observation – that correct pairs are more similar to one another than incorrect pairs are to each other – to the opening line of Leo Tolstoy’s Anna Karenina, which states, “All happy families are alike; each unhappy family is unhappy in its own way.”

    The work was done using protein sequences from bacteria, and the researchers are now extending the technique to other organisms.

    The approach has the potential to enhance the systematic study of biology, Wingreen said. “We know that living organisms are based on networks of interacting proteins,” he said. “Finally we can begin to use sequence data to explore these networks.”

    The research was supported in part by the National Institutes of Health (Grant R01-GM082938) and the National Science Foundation (Grant PHY–1305525).

    See the full article here .

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    Princeton University Campus

    About Princeton: Overview

    Princeton University is a vibrant community of scholarship and learning that stands in the nation’s service and in the service of all nations. Chartered in 1746, Princeton is the fourth-oldest college in the United States. Princeton is an independent, coeducational, nondenominational institution that provides undergraduate and graduate instruction in the humanities, social sciences, natural sciences and engineering.

    As a world-renowned research university, Princeton seeks to achieve the highest levels of distinction in the discovery and transmission of knowledge and understanding. At the same time, Princeton is distinctive among research universities in its commitment to undergraduate teaching.

    Today, more than 1,100 faculty members instruct approximately 5,200 undergraduate students and 2,600 graduate students. The University’s generous financial aid program ensures that talented students from all economic backgrounds can afford a Princeton education.

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  • richardmitnick 9:11 am on September 19, 2016 Permalink | Reply
    Tags: #weekendusers Express experiments for better health, , , Protein Studies   

    From ESRF: “#weekendusers Express experiments for better health” 

    ESRF bloc
    The European Synchrotron


    Synchrotron sources are crucial for structural biology and research performed at the ESRF produces 40% of the protein structures submitted in Europe. This weekend, scientists from Barcelona spent 24 hours trying to unveil the structures of medically-relevant proteins.

    They drove more than 1000km for 24h of experiments and 130 samples. The aim: to get insight into the structures of proteins that play a role in health, such as mycoplasma, viral and membrane transport proteins. “It is very intense”, explains David Aparicio, from the Institut de Biologia Molecular de Barcelona (Spain), “but we are now coming once a month for 24h each time, so we are used to this rythm”, he adds. He is one of the four scientists on ID23-1 this weekend. Two of them, Victor Ruiz and Diego Ferrero, also come from the IBMB, but from different research groups, whilst the last one, Ekaitz Errasti works in the Institute for Research in Biomedicine (IRB) in the same city.

    Checking that the experiment is going smoothly in the small hours of Sunday. No image credit.

    The researchers came to the ESRF in the framework of the so-called Block Allocation Group from Barcelona. Crystallographers from large, well-established groups requiring a significant amount of beamtime often present their proposals in groups. BAG Barcelona includes groups that belong to the Institute for Molecular Biology of Barcelona (IBMB) from the Spanish Reseach Council (CSIC), the Institute of Biomedical Research (IRB) and the Institut de Recerca – Hospital de la Santa Creu i Sant Pau (HSCSP).

    Maria Solà, coordinator of the BAG Barcelona, explains that “the success of our projects is absolutely dependent on obtaining data using synchrotron radiation”, due to the size and characteristics of the samples. “The tunable and microfocus beamline of ID23 fulfills excellently all our requirements”, she adds, “so we are hoping for good data”.

    See the full article here .

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    The ESRF – the European Synchrotron Radiation Facility – is the most intense source of synchrotron-generated light, producing X-rays 100 billion times brighter than the X-rays used in hospitals. These X-rays, endowed with exceptional properties, are produced at the ESRF by the high energy electrons that race around the storage ring, a circular tunnel measuring 844 metres in circumference. Each year, the demand to use these X-ray beams increases and thousands of scientists from around the world come to Grenoble, to access the 43 highly specialised experimental stations, called “beamlines”, each equipped with state-of-the-art instrumentation, operating 24 hours a day, seven days a week.

    Thanks to the brilliance and quality of its X-rays, the ESRF functions like a “super-microscope” which “films” the position and motion of atoms in condensed and living matter, and reveals the structure of matter in all its beauty and complexity. It provides unrivalled opportunities for scientists in the exploration of materials and living matter in a very wide variety of fields: chemistry, material physics, archaeology and cultural heritage, structural biology and medical applications, environmental sciences, information science and nanotechnologies.

    Following on from 20 years of success and excellence, the ESRF has embarked upon an ambitious and innovative modernisation project, the Upgrade Programme, implemented in two phases: Phase I (2009-2015) and the ESRF-EBS (Extremely Brilliant Source) (2015-2022) programmes. With an investment of 330 million euros, the Upgrade Programme is paving the way to a new generation of synchrotron storage rings, that will produce more intense, coherent and stable X-ray beams. By constructing a new synchrotron, deeply rooted in the existing infrastructure, the ESRF will lead the way in pushing back the boundaries of scientific exploration of matter, and contribute to answering the great technological, economic, societal and environmental challenges confronting our society.

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