From Argonne APS: "Protein Structure Could Lead to Better Treatments for HIV, Early Aging"

News from Argonne National Laboratory

APRIL 9, 2013
No Writer Credit

“Researchers have determined the molecular structure of a protein whose mutations have been linked to several early aging diseases, and side effects for common human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) medications. This breakthrough could eventually help researchers develop new treatments for these early-aging diseases and redesign AIDS medications to avoid side effects such as diabetes. The research was carried out at the Southeastern Regional Collaborative Access Team(SER-CAT) facility at the U.S. Department of Energy Office of Science’s Advanced Photon Source (APS) at Argonne National Laboratory.

Ribbon diagram of the Ste24p protease.

The researchers from the University of Virginia School of Medicine, the Hauptman-Woodward Medical Research Institute, and the University of Rochester School of Medicine and Dentistry determined the molecular structure of the enzyme Ste24p. Their Membrane Protein Structural Biology Consortium is funded by the National Institutes of Health Protein Structure Initiative, which supports the determination of molecular structures of biomedically important target proteins. Their findings were published March 29 in the journal Science.

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

The Advanced Photon Source at Argonne National Laboratory is one of five national synchrotron radiation light sources supported by the U.S. Department of Energy’s Office of Science to carry out applied and basic research to understand, predict, and ultimately control matter and energy at the electronic, atomic, and molecular levels, provide the foundations for new energy technologies, and support DOE missions in energy, environment, and national security.

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From Brookhaven Lab: “Structure Helps Yield Drug ‘Hypersensitivity’ Tests for Patients”

Brookhaven Lab

April 8, 2013
Laura Mgrdichian

“From a patient’s point of view, one of the unsettling things about taking a new drug is the possibility of unwelcome side effects or worse, dangerous allergic reactions. As drugs are being developed and then enter clinical trials, these issues play a huge role in the process, increasing costs and sometimes determining whether a drug will get to market at all.

In this “ribbon diagram,” the HIV/AIDS drug abacavir (orange, blue and red spheres) interacts with a protein (grey) made by a particular gene that causes a hypersensitivity to the drug. The protein “shows” the body’s immune system a peptide (light blue) it has never seen, causing an allergic reaction. No image credit.

One type of severe reaction is ‘hypersensitivity,’ in which the immune system over-reacts to a substance that is foreign but not infectious, producing symptoms that can be mild (such as rashes) to severe (organ failure, even death). In this study, researchers studied an antiviral drug known to cause hypersensitivity in patients who carry a particular gene. Using x-rays at Brookhaven Lab’s National Synchrotron Light Source (NSLS), they were able to ‘see’ how at the molecular level, the drug binds to the protein created from the gene, triggering the immune response. Their work has produced new ways to predict whether a drug is likely to induce a gene-based allergic reaction.”

See the full article here.

One of ten national laboratories overseen and primarily funded by the Office of Science of the U.S. Department of Energy (DOE), Brookhaven National Laboratory conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies and national security. Brookhaven Lab also builds and operates major scientific facilities available to university, industry and government researchers. The Laboratory’s almost 3,000 scientists, engineers, and support staff are joined each year by more than 5,000 visiting researchers from around the world.Brookhaven is operated and managed for DOE’s Office of Science by Brookhaven Science Associates, a limited-liability company founded by Stony Brook University, the largest academic user of Laboratory facilities, and Battelle, a nonprofit, applied science and technology organization.

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From Berkeley Lab: “Sweet Success”

Berkeley Lab

Berkeley Lab Researchers Find Way to Catalyze More Sugars from Biomass

April 07, 2013
Lynn Yarris (510) 486-5375 lcyarris@lbl.gov

“Catalysis may initiate almost all modern industrial manufacturing processes, but catalytic activity on solid surfaces is poorly understood. This is especially true for the cellulase enzymes used to release fermentable sugars from cellulosic biomass for the production of advanced biofuels. Now, researchers with the Lawrence Berkeley National Laboratory (Berkeley Lab) through support from the Energy Biosciences Institute (EBI) have literally shed new light on cellulase catalysis.

PALM – for Photo-Activated Localization Microscopy – enables researchers to quantify how and where enzymes are binding to the surface of cellulose in heterogeneous surfaces, such as those in plant cell walls.

Using an ultrahigh-precision visible light microscopy technique called PALM – for Photo-Activated Localization Microscopy – the researchers have found a way to improve the collective catalytic activity of enzyme cocktails that can boost the yields of sugars for making fuels. Increasing the sugar yields from cellulosic biomass to help bring down biofuel production costs is essential for the widespread commercial adoption of these fuels.

From left, Jan Liphardt, Harvey Blanch and Doug Clark led the development of a way to improve the collective catalytic activity of enzyme cocktails that can boost the yields of sugars for making advanced biofuels. (Photo by Roy Kaltschmidt)

‘The enzymatic breakdown of cellulosic biomass into fermentable sugars has been the Achilles heel of biofuels, a key economic bottleneck,’ says chemical engineer Harvey Blanch, one of the leaders of this research. ‘Our research provides a new understanding of how multiple cellulase enzymes attack solid cellulose by working in concert, an action known as enzyme synergy, and explains why certain mixtures of cellulase enzymes work better together than each works individually.’”

See the full article here.

A U.S. Department of Energy National Laboratory Operated by the University of California

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From Argonne APS: “Antibody evolution could guide HIV vaccine development”

News from Argonne National Laboratory

“Observing the evolution of a particular type of antibody in an infected HIV-1 patient has provided insights that will enable vaccination strategies that mimic the actual antibody development within the body. Spearheaded by Duke University, the multi-institution study included analysis from Los Alamos National Laboratory and used high-energy X-rays from the Advanced Photon Source at Argonne National Laboratory.

The evolution of the viral protein (green) from 14 weeks through 100 weeks post-transmission is compared with the maturation of the human antibody.

The kind of antibody studied is called a broadly cross-reactive neutralizing antibody, and details of its generation could provide a blueprint for effective vaccination, according to the study’s authors. In a paper published online in Nature this week titled Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus, the team reported on the isolation, evolution and structure of a broadly neutralizing antibody from an African donor followed from the time of infection.

The observations trace the co-evolution of the virus and antibodies, ultimately leading to the development of a strain of the potent antibodies in this subject, and they could provide insights into strategies to elicit similar antibodies by vaccination.

Patients early in HIV-1 infection have primarily a single “founder” form of the virus that has been strong enough to infect the patient, even though the population in the originating patient is usually far more diverse and contains a wide variety of HIV mutations. Once the founder virus is involved in the new patient’s system, the surrounding environment stimulates the HIV to mutate and form a unique, tailored population of virus that is specific to the individual.

‘Our hope is that a vaccine based on the series of HIV variants that evolved within this subject, that were together capable of stimulating this potent broad antibody response in his natural infection, may enable triggering similar protective antibody responses in vaccines,’ said [Bette] Korber, leader of the Los Alamos team.”

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

The Advanced Photon Source at Argonne National Laboratory is one of five national synchrotron radiation light sources supported by the U.S. Department of Energy’s Office of Science to carry out applied and basic research to understand, predict, and ultimately control matter and energy at the electronic, atomic, and molecular levels, provide the foundations for new energy technologies, and support DOE missions in energy, environment, and national security.

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From Sandia Lab: “New instrument will quickly detect botulinum, ricin, other biothreat agents”

” Researchers at Sandia National Laboratories are developing a medical instrument that will be able to quickly detect a suite of biothreat agents, including anthrax, ricin, botulinum, shiga and SEB toxin.

From left to right, Sandia National Laboratories’ Matt Piccini, Chung-Yan Koh and Anup Singh lead the SpinDx team. A new National Institutes of Health-funded project will take the device to a new level and is expected to result in an instrument that can detect a suite of biothreat agents. (Photo by Jeff McMillan)

The device, once developed, approved by the Food and Drug Administration and commercialized, would most likely be used in emergency rooms in the event of a bioterrorism incident.

‘This is an unmet need for the nation’s biodefense program,’ said Anup Singh, senior manager for Sandia’s biological science and technology group. ‘A point-of-care device does not exist.’

Sandia’s work is funded by a recent grant – nearly $4 million over four years – from the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health. NIH has funded a number of recent projects at Sandia.

Sandia National Laboratories is a multiprogram laboratory operated by Sandia Corporation, a wholly owned subsidiary of Lockheed Martin Corporation, for the U.S. Department of Energy’s National Nuclear Security Administration. With main facilities in Albuquerque, N.M., and Livermore, Calif., Sandia has major R&D responsibilities in national security, energy and environmental technologies, and economic competitiveness.

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From PNNL Lab: “Striking While the Iron Is Hot”

Chromatography combined with database search strategy identifies hard-to-find heme proteins

March 2013
Suraiya Farukhi
Christine Sharp

“Results: Heme c is an important iron-containing post-translational modification found in many proteins. It plays an important role in respiration, metal reduction, and nitrogen fixation, especially anaerobic respiration of environmental microbes. Such bacteria and their c-type cytochromes are studied extensively because of their potential use in bioremediation, microbial fuel cells, and electrosynthesis of valuable biomaterials.

Heme C

Until recently, these modifications were hard to find using traditional proteomic methods. Scientists at Pacific Northwest National Laboratory combined a heme c tag protein affinity purification strategy called histidine affinity chromatography (HAC) with enhanced database searching. This combination confidently identified heme c peptides in liquid chromatography-tandem mass spectrometry (LC-MS/MS) experiments-by as much as 100-fold in some cases.”

Why It Matters: Iron is a critical part of many biological processes; however, it is often not biologically available or it can be toxic in high quantities. So, biological systems have developed intricate methods to use and store iron. Many environmentally important microbes and microbial communities are rich in c-type cytochromes. Combining HAC and data analysis tailored to the unique properties of heme c peptides should enable more detailed study of the role of c-type cytochromes in these microbes and microbial communities.

‘Several proteomics studies have analyzed the expression of c-type cytochromes under various conditions,’ said PNNL postdoctoral researcher Dr. Eric Merkley, and lead author of a paper that appeared in the Journal of Proteome Research. ‘A shared feature of these studies is that the cytochrome-rich fractions, the cell envelope or extracellular polymeric substance, were purified and explicitly analyzed to efficiently detect cytochromes. Analyses of large-scale proteomics datasets have typically suggested that c-type cytochromes, particularly the heme c peptides, are under-represented.’”

See the full article here.

Pacific Northwest National Laboratory (PNNL) is one of the United States Department of Energy National Laboratories, managed by the Department of Energy’s Office of Science. The main campus of the laboratory is in Richland, Washington.

PNNL scientists conduct basic and applied research and development to strengthen U.S. scientific foundations for fundamental research and innovation; prevent and counter acts of terrorism through applied research in information analysis, cyber security, and the nonproliferation of weapons of mass destruction; increase the U.S. energy capacity and reduce dependence on imported oil; and reduce the effects of human activity on the environment. PNNL has been operated by Battelle Memorial Institute since 1965.

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From Caltech: “Developing Our Sense of Smell”

Caltech

03/25/2013
Katie Neith

Caltech biologists pinpoint the origin of olfactory nerve cells

“When our noses pick up a scent, whether the aroma of a sweet rose or the sweat of a stranger at the gym, two types of sensory neurons are at work in sensing that odor or pheromone. These sensory neurons are particularly interesting because they are the only neurons in our bodies that regenerate throughout adult life—as some of our olfactory neurons die, they are soon replaced by newborns. Just where those neurons come from in the first place has long perplexed developmental biologists.

Image of 2.5-um thick optical slice through the nose of a zebrafish embryo in which microvillous (green) cells also are stained with a neuronal marker (red) demonstrating their neuronal identify. Nuclei are stained in blue. Scale bar: 30 μm.
Credit: Courtesy of Ankur Saxena/Caltech

‘Olfactory neurons have long been thought to be solely derived from a thickened portion of the ectoderm; our results directly refute that concept,’ says Marianne Bronner, the Albert Billings Ruddock Professor of Biology at Caltech and corresponding author of a paper published in the journal eLIFE on March 19 that outlines the findings.”

See the full article here.

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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From Berkeley Lab: “Computer Simulations Yield Clues to How Cells Interact With Surroundings”

Berkeley Lab

Berkeley Lab research has implications for cancer, atherosclerosis research

March 21, 2013
Dan Krotz

“Your cells are social butterflies. They constantly interact with their surroundings, taking in cues on when to divide and where to anchor themselves, among other critical tasks.

This networking is driven in part by proteins called integrin, which reside in a cell’s outer plasma membrane. Their job is to convert mechanical forces from outside the cell into internal chemical signals that tell the cell what to do. That is, when they work properly. When they misfire, integrins can cause diseases such as atherosclerosis and several types of cancer.

Computer models offer a new look at the molecular machinery that enables cells to interact with their environment. This schematic shows two integrin components (red and blue) protruding from a cell membrane. (Credit: Mofrad lab)

Despite their importance—good and bad—scientists don’t exactly know how integrins work. That’s because it’s very difficult to experimentally observe the protein’s molecular machinery in action. Scientists have yet to obtain the entire crystal structure of integrin within the plasma membrane, which is a go-to way to study a protein’s function. Roadblocks like this have ensured that integrins remain a puzzle despite years of research.

But what if there was another way to study integrin? One that doesn’t rely on experimental methods? Now there is, thanks to a computer model of integrin developed by Berkeley Lab researchers. Like its biological counterpart, the virtual integrin snippet is about twenty nanometers long. It also responds to changes in energy and other stimuli just as integrins do in real life. The result is a new way to explore how the protein connects a cell’s inner and outer environments.

‘We can now run computer simulations that reveal how integrins in the plasma membrane translate external mechanical cues to chemical signals within the cell,’ says Mohammad Mofrad, a faculty scientist in Berkeley Lab’s Physical Biosciences Division and associate professor of Bioengineering and Mechanical Engineering at UC Berkeley. He conducted the research with his graduate student Mehrdad Mehrbod.

They report their research in a recent issue of PLoS Computational Biology.

Their ‘molecular dynamics’ model is the latest example of computational biology, in which scientists use computers to analyze biological phenomena for insights that may not be available via experiment. As you’d expect from a model that accounts for the activities of half a million atoms at once, the integrin model takes a lot of computing horsepower to pull off. Some of its simulations require 48 hours of run time on 600 parallel processors at the U.S. Department of Energy’s (DOE) National Energy Research Scientific Computing Center (NERSC), which is located at Berkeley Lab.

The model is already shedding light on what makes integrin tick, such as how they know’ to respond to more force with greater numbers. When activated by an external force, integrins cluster together on a cell’s surface and join other proteins to form structures called focal adhesions. These adhesions recruit more integrins when they’re subjected to higher forces. As the model indicates, this ability to pull in more integrins on demand may be due to the fact that a subunit of integrin is connected to actin filaments, which form a cell’s skeleton.

‘We found that if actin filaments sustain more forces, they automatically bring more integrins together, forming a larger cluster,’ says Mehrbod.

The model may also help answer a longstanding question: Do integrins interact with each other immediately after they’re activated? Or do they not interact with each other at all, even as they cluster together?

‘Our research sets up an avenue for future studies by offering a hypothesis that relates integrin activation and clustering,’ says Mofrad.”

See the full article here.

A U.S. Department of Energy National Laboratory Operated by the University of California

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From PNNL: “Seeing the Messages Microbes Send”

Novel chemical imaging instrument shows how bacteria support diverse, nearby colonies

March 2013
Suraiya Farukhi
Christine Sharp

“Results: With a novel technique that noninvasively analyzes microbes, scientists at Pacific Northwest National Laboratory profiled, for the first time, the chemicals that a cyanobacterium makes available to others. Over 4 days, Synechococcus sp. PCC 7002 steadily secretes two molecules that could be used as resources by other bacteria that are nearby. The technique that chemically profiles the microbial communities in both space and time is Nanospray Desorption Ionization Electrospray Mass Spectrometry, or nano-DESI. This instrument was built by Dr. Julia Laskin and her team at Pacific Northwest National Laboratory. This research graced the cover of Analyst.

Scientists at Pacific Northwest National Laboratory used the nano-DESI to show how bacteria support other colonies. No image credit.

‘This is a tool that will help microbiologists identify molecules that promote or inhibit growth of microbial communities,’ said Lab Fellow Laskin. ‘It also gives us much better control for studying interactions between microbial communities.’

Why It Matters: Understanding microbial ecology — how bacteria, algae and other microbes influence each other — could provide basic answers needed to advance sustainable energy. For example, Synechococcus sp. PCC 7002 uses carbon dioxide and sunlight to produce sugars that fuel the colony. Knowing how to best grow and modify these bacteria to mass-produce fuels could increase our nation’s energy independence. Here, nano-DESI provides key data for sustainable energy, but the opportunities stretch much farther.

‘Any place where there are microbes and you have a format where nano-DESI could be applied, you can study that ecology,’ said Dr. Allan Konopka, a biologist and Lab Fellow at PNNL who worked on the study. ‘This opens doors to a host of applications, such as understanding how bacteria associated with plant roots affect a plant.’”

Pacific Northwest National Laboratory (PNNL) is one of the United States Department of Energy National Laboratories, managed by the Department of Energy’s Office of Science. The main campus of the laboratory is in Richland, Washington.

PNNL scientists conduct basic and applied research and development to strengthen U.S. scientific foundations for fundamental research and innovation; prevent and counter acts of terrorism through applied research in information analysis, cyber security, and the nonproliferation of weapons of mass destruction; increase the U.S. energy capacity and reduce dependence on imported oil; and reduce the effects of human activity on the environment. PNNL has been operated by Battelle Memorial Institute since 1965.

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From Argonne: “Watching a Protein as it Functions”

News from Argonne National Laboratory

MARCH 14, 2013
Mona Mort

“When it comes to understanding how proteins perform their amazing cellular feats, it is often the case that the more one knows the less one realizes they know. For decades, biochemists and biophysicists have worked to reveal the relationship between protein structural complexity and function, only to discover more complexity. One challenging aspect of protein behavior has been the speed with which they change shape and interact with their neighboring biomolecules. Until recently, researchers have relied on a somewhat static approach, using freeze-trapping to capture protein intermediates at various steps along a biochemical pathway. But exciting breakthroughs now allow us to watch proteins changing in real time.

The PYP structure in its ground (pG) state: Arrows point to the pCA C2=C3 double bond and the Ca atoms of key residues. Hydrogen bonds are indicated with dashed blue lines. Arg52 is stabilized in its “closed” state via hydrogen bonds to the protein backbone.No image credit

A research group has developed the necessary infrastructure at the BioCARS 14-ID-B beamline at the U.S. Department of Energy Office of Science’s Advanced Photon Source to watch proteins function in real time on the picosecond time scale. Their work brings us many steps closer to knowing how proteins function, or malfunction when leading to disease.”

See the full article here.

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

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