DOE News
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    The DOE Science News Source is a Newswise initiative to promote research news from the Office of Science of the DOE to the public and news media.
    • 2015-08-13 15:05:00
    • Article ID: 638629

    Scientists Discover Atomic-Resolution Details of Brain Signaling

    X-ray Laser Experiment Could Help in Designing New Drugs for Brain Disorders

    • Credit: SLAC National Accelerator Laboratory

      This illustration shows a protein complex at work in brain signaling. Its structure, which contains joined protein complexes known as SNARE and synaptotagmin-1, is shown in the foreground. This complex is responsible for the calcium-triggered release of neurotransmitters from our brain’s nerve cells in a process called synaptic vesicle fusion. The SNARE structure is shown in blue, red, and green, and synaptotagmin-1 is shown in orange. The background image shows electrical signals traveling through a neuron.

    • Credit: SLAC National Accelerator Laboratory

      From left, Axel Brunger, Artem Lyubimov, Qiangjun “John” Zhou and Minglei Zhao view images from an experiment at SLAC’s Linac Coherent Light Source, an X-ray free-electron laser. Researchers used a robotic setup to zap tiny, frozen crystals (the screen at upper left shows one crystal) with a series of X-ray pulses. They analyzed X-ray images of these crystals to determine the atomic-scale structure of a protein complex that provides clues to how our brains send rapid chemical messages.

    • Credit: SLAC National Accelerator Laboratory

      Equipment used in a highly automated, robotic X-ray crystallography system at SLAC's Linac Coherent Light Source X-ray laser. The metal drum at lower left contains liquid nitrogen for cooling crystallized samples studied with LCLS's intense X-ray pulses. This setup was used in an experiment exploring the molecular machinery involved in brain signaling in atomic-scale detail.

    • Credit: SLAC National Accelerator Laboratory

      This image shows a crystal, measuring less than 1 millimeter across, that was used in an X-ray laser experiment at SLAC. The series of dark lines shows where X-ray laser pulses struck the frozen crystal. Researchers used images generated by X-rays striking this crystal to help map the 3-D atomic structure of the protein complex it contains.

    • Credit: SLAC National Accelerator Laboratory

      This illustration shows a protein complex at work in brain signaling. Its structure, which contains joined protein complexes known as SNARE and synaptotagmin-1, is shown in the foreground. This complex is responsible for the calcium-triggered release of neurotransmitters from our brain’s nerve cells in a process called synaptic vesicle fusion. The SNARE structure is shown in blue, red, and green, and synaptotagmin-1 is shown in orange. The background image shows electrical signals traveling through a neuron.

    Menlo Park, Calif. — Scientists have revealed never-before-seen details of how our brain sends rapid-fire messages between its cells. They mapped the 3-D atomic structure of a two-part protein complex that controls the release of signaling chemicals, called neurotransmitters, from brain cells. Understanding how cells release those signals in less than one-thousandth of a second could help launch a new wave of research on drugs for treating brain disorders.

    The experiments, at the Linac Coherent Light Source (LCLS) X-ray laser at the Department of Energy’s SLAC National Accelerator Laboratory, build upon decades of previous research at Stanford University, Stanford School of Medicine and SLAC. Researchers reported their latest findings today in the journal Nature.

    “This is a very important, exciting advance that may open up possibilities for targeting new drugs to control neurotransmitter release. Many mental disorders, including depression, schizophrenia and anxiety, affect neurotransmitter systems,” said Axel Brunger, the study’s principal investigator. He is a professor at Stanford School of Medicine and SLAC and a Howard Hughes Medical Institute investigator.

    “Both parts of this protein complex are essential,” Brunger said, “but until now it was unclear how its two pieces fit and work together.”

    Unraveling the Combined Secrets of Two Proteins

    The two protein parts are known as neuronal SNAREs and synaptotagmin-1.

    Earlier X-ray studies, including experiments at SLAC’s Stanford Synchrotron Radiation Lightsource (SSRL) nearly two decades ago, shed light on the structure of the SNARE complex, a helical protein bundle found in yeasts and mammals. SNAREs play a key role in the brain’s chemical signaling by joining, or “fusing,” little packets of neurotransmitters to the outer edges of neurons, where they are released and then dock with chemical receptors in another neuron to trigger a response.

    A ‘Smoking Gun’ for Neurotransmitter Release

    In this latest research, the scientists found that when the SNAREs and synaptotagmin-1 join up, they act as an amplifier for a slight increase in calcium concentration, triggering a gunshot-like release of neurotransmitters from one neuron to another. They also learned that the proteins join together before they arrive at a neuron’s membrane, which helps to explain how they trigger brain signaling so rapidly.

    “The neuron is not building the ‘gun’ as it sits there on the membrane – it’s already there,” Brunger said.

    The team speculates that several of the joined protein complexes may group together and simultaneously interact with the same vesicle to efficiently trigger neurotransmitter release, an exciting area for further studies.

    “The structure of the SNARE-synaptotagmin-1 complex is a milestone that the field has awaited for a long time, and it sets the framework for a better understanding of the system,” said James Rothman, a professor at Yale University who discovered the SNARE proteins and shared the 2013 Nobel Prize in Physiology or Medicine.

    Thomas C. Südhof, a professor at the Stanford School of Medicine and Howard Hughes Medical Institute investigator who shared that 2013 Nobel Prize with Rothman, discovered synaptotagmin-1 and showed that it plays an important role as a calcium sensor and calcium-dependent trigger for neurotransmitter release.

    “The new structure has identified unanticipated interfaces between synaptotagmin-1 and the neuronal SNARE complex that change how we think about their interaction by revealing, in atomic detail, exactly where they bind together,” Südhof said. “This is a new concept that goes much beyond previous general models of how synaptotagmin-1 functions.”

    Using Crystals, Robotics and X-rays to Advance Neuroscience

    To study the joined protein structure, researchers in Brunger’s laboratory at the Stanford School of Medicine found a way to grow crystals of the complex. They used a robotic system developed at SSRL to study the crystals at SLAC’s LCLS, an X-ray laser that is one of the brightest sources of X-rays on the planet. SSRL and LCLS are DOE Office of Science User Facilities.

    The researchers combined and analyzed hundreds of X-ray images from about 150 protein crystals to reveal the atomic-scale details of the joined structure.

    SSRL’s Aina Cohen, who oversaw the development of the highly automated platform used for the neuroscience experiment, said, “This experiment was the first to use this robotic platform at LCLS to determine a previously unsolved structure of a large, challenging multi-protein complex.” The study was also supported by X-ray experiments at SSRL and at Argonne National Laboratory’s Advanced Photon Source.

    “This is a good example of how advanced tools, instruments and X-ray methods are providing us new insights into what are truly complex mechanisms,” Cohen said.

    Brunger said future studies will explore other protein interactions relevant to neurotransmitter release. “What we studied is only a subset,” he said. “There are many other factors interacting with this system and we want to know what these look like. This by no means is the end of the story.”

    In addition to researchers at SLAC, Stanford University and the Stanford School of Medicine, other contributing scientists were from Lawrence Berkeley National Laboratory. The research was supported by the Howard Hughes Medical Institute; the National Institutes of Health (NIH); the DOE Office Science; and the SSRL Structural Molecular Biology Program, which is also supported by the DOE Office of Science and the NIH’s National Institute of General Medical Sciences.

    SLAC is a multi-program laboratory exploring frontier questions in photon science, astrophysics, particle physics and accelerator research. Located in Menlo Park, California, SLAC is operated by Stanford University for the U.S. Department of Energy Office of Science. To learn more, please visit www.slac.stanford.edu.

    SLAC National Accelerator Laboratory is supported by the Office of Science of the U.S. Department of Energy. The 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. For more information, please visit science.energy.gov.

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    Here, There and Everywhere: Large and Giant Viruses Abound Globally

    Here, There and Everywhere: Large and Giant Viruses Abound Globally

    In Nature, a team led by U.S. Department of Energy (DOE) Joint Genome Institute (JGI) researchers uncovered a broad diversity of large and giant viruses that belong to the nucleocytoplasmic large DNA viruses (NCLDV) supergroup, expanding virus diversity in this group 10-fold from just 205 genomes.

    Chemistry finding could make solar energy more efficient

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    New model helps pave the way to bringing clean fusion energy down to Earth

    New model helps pave the way to bringing clean fusion energy down to Earth

    State-of-the-art simulation confirms a key source of heat and energy loss in spherical fusion facilities.

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    Rising global temperatures turn northern permafrost region into significant carbon source

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    Scientists pioneer new generation of semiconductor neutron detector

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    Astrophysicists have come a step closer to understanding the origin of a faint glow of gamma rays covering the night sky. They found that this light is brighter in regions that contain a lot of matter and dimmer where matter is sparser - a correlation that could help them narrow down the properties of exotic astrophysical objects and invisible dark matter.

    Nano-objects of Desire: Assembling Ordered Nanostructures in 3-D

    Nano-objects of Desire: Assembling Ordered Nanostructures in 3-D

    A new DNA-programmable nanofabrication platform organizes inorganic or biological nanocomponents in the same prescribed ways.


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    Lin Chen receives Award in Experimental Physical Chemistry

    Lin Chen receives Award in Experimental Physical Chemistry

    The Physical Chemistry Division of the American Chemical Society announces that Lin X. Chen has received the 2020 Award in Experimental Physical Chemistry. The award recognizes Chen for "fundamental contributions to the elucidation of excited state structures, dynamics and energetics of light harvesting systems.

    Polymer expert Advincula named ORNL-UT Governor's Chair

    Polymer expert Advincula named ORNL-UT Governor's Chair

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    Former PPPL intern honored for outstanding machine learning poster

    Former PPPL intern honored for outstanding machine learning poster

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    Team led by PPPL wins major supercomputer time to help capture on Earth the fusion that powers the sun and stars

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    PPPL will use INCITE-award time on Summit and Theta supercomputers to develop predictions for the performance of ITER, the international experiment under construction to demonstrate the feasibility of fusion energy.

    Department of Energy Announces $625 Million for New Quantum Centers

    The U.S. Department of Energy (DOE) announced up to $625 million over the next five years to establish two to five multidisciplinary Quantum Information Science (QIS) Research Centers in support of the National Quantum Initiative.

    Department of Energy to Provide $75 Million for Bioenergy Crops Research

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    Jefferson Lab to be Major Partner in Electron Ion Collider Project

    Jefferson Lab to be Major Partner in Electron Ion Collider Project

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    Department of Energy Selects Site for Electron-Ion Collider

    Department of Energy Selects Site for Electron-Ion Collider

    UPTON, NY-- Yesterday, the U.S. Department of Energy (DOE) named Brookhaven National Laboratory on Long Island in New York as the site for building an Electron-Ion Collider (EIC), a one-of-a-kind nuclear physics research facility. This announcement, following DOE's approval of "mission need" (known as Critical Decision 0) on December 19, 2019, enables work to begin on R&D and the conceptual design for this next-generation collider at Brookhaven Lab.

    Department of Energy Announces $32 Million for Small Business Research and Development Grants

    U.S. Secretary of Energy Dan Brouillette announced that the Department of Energy (DOE) will award 158 grants totaling $32 million to 118 small businesses in 32 states. Funded through DOE's Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) programs, these selections are for Phase I research and development.

    Summit Charts a Course to Uncover the Origins of Genetic Diseases

    Summit Charts a Course to Uncover the Origins of Genetic Diseases

    Gene mutations can interfere with how the body expresses genes and cause disease. To better understand this connection, researchers recently developed a model of the transcription preinitiation complex (PIC).


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    Harvesting Energy from Light using Bio-inspired Artificial Cells

    Harvesting Energy from Light using Bio-inspired Artificial Cells

    Scientists designed and connected two different artificial cells to each other to produce molecules called ATP (adenosine triphosphate).

    Engineering Living Scaffolds for Building Materials

    Engineering Living Scaffolds for Building Materials

    Bone and mollusk shells are composite systems that combine living cells and inorganic components. This allows them to regenerate and change structure while also being very strong and durable. Borrowing from this amazing complexity, researchers have been exploring a new class of materials called engineered living materials (ELMs).

    Excavating Quantum Information Buried in Noise

    Excavating Quantum Information Buried in Noise

    Researchers developed two new methods to assess and remove error in how scientists measure quantum systems. By reducing quantum "noise" - uncertainty inherent to quantum processes - these new methods improve accuracy and precision.

    How Electrons Move in a Catastrophe

    How Electrons Move in a Catastrophe

    Lanthanum strontium manganite (LSMO) is a widely applicable material, from magnetic tunnel junctions to solid oxide fuel cells. However, when it gets thin, its behavior changes for the worse. The reason why was not known. Now, using two theoretical methods, a team determined what happens.

    When Ions and Molecules Cluster

    When Ions and Molecules Cluster

    How an ion behaves when isolated within an analytical instrument can differ from how it behaves in the environment. Now, Xue-Bin Wang at Pacific Northwest National Laboratory devised a way to bring ions and molecules together in clusters to better discover their properties and predict their behavior.

    Tune in to Tetrahedral Superstructures

    Tune in to Tetrahedral Superstructures

    Shape affects how the particles fit together and, in turn, the resulting material. For the first time, a team observed the self-assembly of nanoparticles with tetrahedral shapes.

    Tracing Interstellar Dust Back to the Solar System's Formation

    Tracing Interstellar Dust Back to the Solar System's Formation

    This study is the first to confirm dust particles pre-dating the formation of our solar system. Further study of these materials will enable a deeper understanding of the processes that formed and have since altered them.

    Investigating Materials that Can Go the Distance in Fusion Reactors

    Investigating Materials that Can Go the Distance in Fusion Reactors

    Future fusion reactors will require materials that can withstand extreme operating conditions, including being bombarded by high-energy neutrons at high temperatures. Scientists recently irradiated titanium diboride (TiB2) in the High Flux Isotope Reactor (HFIR) to better understand the effects of fusion neutrons on performance.

    Better 3-D Imaging of Tumors in the Breast with Less Radiation

    Better 3-D Imaging of Tumors in the Breast with Less Radiation

    In breast cancer screening, an imaging technique based on nuclear medicine is currently being used as a successful secondary screening tool alongside mammography to improve the accuracy of the diagnosis. Now, a team is hoping to improve this imaging technique.

    Microbes are Metabolic Specialists

    Microbes are Metabolic Specialists

    Scientists can use genetic information to measure if microbes in the environment can perform specific ecological roles. Researchers recently analyzed the genomes of over 6,000 microbial species.


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