Archive by category: News and Updates

Emad Tajkhorshid and co-PIs at UIUC recipients of NIH High-Risk, High-Reward Research

University of Illinois professor and MPSDC team member Emad Tajkhorshid, along with co-PIs Chad Rienstra (Chemistry) and James Morrissey (Biochemistry) have been awarded a Director’s Transformative Research Award from the National Institutes of Health for their highly creative approach to the study of cell membrane lipids.

Membrane proteins are abundant in eukaryotic cells and play important roles in a great many biological processes ranging from cell adhesion and recognition to energy production to signaling cascades. 

Membrane proteins make up more than half of the targets for currently approved drugs, which underscores their relevance to human disease but less is known about the membrane lipids that interact with proteins and ligands.

It is becoming increasingly clear that lipids are effector molecules that modulate and/or directly carry out essential biological functions at very different rates depending on what types of lipids are present. Some examples include blood clotting, cell recognition (in immunological response especially), ion conduction (important for neuronal function and viral infection), transport of drugs across the membrane, and pain response.

A potential long-term application is the development of more effective drugs that target biological membranes. Since about 60% of the drugs on the market target membrane-bound proteins, a better understanding of lipid structure and dynamics could greatly improve the efficacy of drug design efforts by modeling the interactions that take place. This would have broader impacts on understanding all the biological functions above and potentially to address the resulting pathologies or diseases. Better blood thinners would help to ameliorate deep vein thrombosis, heart attacks and strokes. Improved modeling of immunological cell recognition and viral life cycles would help to address infectious diseases ranging from influenza to HIV/AIDS. Understanding how drugs are transported would aid in the development of better antibiotics. The project aims to develop a toolkit of methods that would be available to researchers addressing this range of problems and many others.

The High-Risk, High-Reward Research (HRHR) program, supported by the National Institutes of Health (NIH’s Common Fund) awarded twelve transformative research awards funded by the Director’s office. The awards span the broad mission of the NIH and include groundbreaking research.

Read more about the project here: link

In memory: Klaus Schulten

Klaus Schulten, professor of physics and Beckman Institute faculty member for nearly 25 years, has died after an illness. Schulten, who led the Theoretical and Computational Biophysics Group, was a leader in the field of biophysics, conducting seminal work in the area of molecular dynamics simulations, illuminating biological processes and structures in ways that weren’t possible before. His research focused on the structure and function of supramolecular systems in the living cell, and on the development of non-equilibrium statistical mechanical descriptions and efficient computing tools for structural biology. Schulten received his Ph.D. from Harvard University in 1974. At Illinois, he was Swanlund Professor of Physics and was affiliated with the Department of Chemistry as well as with the Center for Biophysics and Computational Biology; he was Director of the Biomedical Technology Research Center for Macromolecular Modeling and Bioinformatics as well as Co-Director of the Center for the Physics of Living Cells.

A memorial service and reception was held November 7. The Beckman Institute will host an honorary symposium in 2017.

Benoît Roux, PI of the MPSDC Computational Modeling Core of which Schulten was an active contributor, shares the following words:

Understanding how biological macromolecular systems (proteins, nucleic acids, membranes) function in terms of their atomic structure represents an outstanding challenge for computational chemists and biophysicists. In this regards, the groundbreaking achievements of Klaus Schulten in Biophysics have opened the door to an unprecedented understanding of biological macromolecular machines. Thanks to the pioneering work of Klaus Schulten, models rigorously anchored in physical laws are now an intrinsic part of life sciences. Because of his intellectual leadership, the complexity of biological systems that can be simulated goes well beyond anything one would have dreamed just a few years ago. By his outstanding contributions, Klaus Schulten has changed the paradigm of computational science and molecular dynamics simulations of complex molecular systems. His tragic loss will long resonate throughout our community.

But Klaus was more than a great scientist, for many of us he was also a close friend. He was great company, and a very collegial and generous member of our community. We will cherish all these memories with him forever.

Solving a Major Piece of a Cellular Mystery about Nuclear Pore Complexes

Drs. Shohei Koide and Anthony Kossiakoff recently worked together with a team to determines the architecture of a second subcomplex of the nuclear pore complex, in so doing solving a major quandary of answering how a nuclear pore complex (NPC) can be such an effective gatekeeper, preventing much from entering the nucleus while helping to shuttle certain molecules across the nuclear envelope.

The scientific team was featured in multiple publications including Caltech and the Argonne National Laboratory Science Highlights (reproduced in part below). The research was supported in part by the Consortium, and culminated in the following publication:

Architecture of the fungal nuclear pore inner ring complex

Stuwe T, Bley CJ, Thierbach K, Petrovic S, Schilbach S, Mayo DJ, Perriches T, Rundlet EJ, Jeon YE, Collins LN, Huber FM, Lin DH, Paduch M, Koide A, Lu V, Fischer J, Hurt E, Koide S, Kossiakoff AA, Hoelz A. Science. 2015 Oct 2;350(6256):56-64. PMID: 26316600.

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Solving a Major Piece of a Cellular Mystery

This article by Argonne reproduced in part can be read here

Not just anything is allowed to enter the nucleus, the heart of eukaryotic cells where, among other things, genetic information is stored. A double membrane, called the “nuclear envelope,” serves as a wall, protecting the contents of the nucleus. Any molecules trying to enter or exit the nucleus must do so via a cellular gatekeeper known as the nuclear pore complex (NPC), or pore, which exists within the envelope.

How can the NPC be such an effective gatekeeper — preventing much from entering the nucleus while helping to shuttle certain molecules across the nuclear envelope? Scientists have been trying to figure that out for decades, at least in part because the NPC is targeted by a number of diseases, including some aggressive forms of leukemia and nervous system disorders such as a hereditary form of Lou Gehrig’s disease. Now a team of researchers from Caltech, The University of Chicago, and the Biochemistry Center of Heidelberg University (Germany), led by André Hoelz and working at three U.S. Department of Energy synchrotron light sources including the Advanced Photon Source (APS) at Argonne, has solved a crucial piece of the puzzle.

In February of this 2015, the team published a paper describing the atomic structure of the NPC’s coat nucleoporin complex, a subcomplex that forms what they now call the outer rings (see the figure). Building on that work, the team has now solved the architecture of the pore’s inner ring, a subcomplex that is central to the NPC’s ability to serve as a barrier and transport facilitator. In order to determine that architecture, which determines how the ring’s proteins interact with each other, the biochemists built up the complex in a test tube and then systematically dissected it to understand the individual interactions between components. Then they validated that this is actually how it works in vivo, in a species of fungus.

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Researchers discover structure of fluoride-specific ion channel

Dr. Shohei Koide‘s collaborations in a scientific team seeking to discover the structure of a fluoride-specific ion channel was recently featured in Brandeis NOW, a scientific research publication published by Brandeis University. The work focuses on Dr. Christopher Miller’s lab, based at Brandeis University. The research was supported in part by the Consortium, and culminated in the following publication:

Crystal structures of a double-barrelled fluoride ion channel

Stockbridge RB, Kolmakova-Partensky L, Shane T, Koide A, Koide S, Miller C, Newstead S. Nature. 2015 Sep 24;525(7570):548-51. PMID: 26344196.

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Researchers discover structure of fluoride-specific ion channel

Creation of ‘atomic blueprint’ is a biological novelty

The original Brandeis NOW press release by Kimm Fesenmaier can be read here

Fluoride protects our teeth against cavity-causing bacteria by making our teeth stronger. But what if we could find a way to trap fluoride ions (the negatively charged form of the chemical element fluorine) inside bacteria? At the right concentration, fluoride ions are highly toxic to bacteria, wreaking havoc on their proteins and disrupting critical cellular functions. Bacteria, however, can fight back, exporting the toxic fluoride ions out using specialized proteins called fluoride-specific ion channels.

How these proteins remove fluoride ions from the cell is poorly understand. To glimpse into the inner workings of these proteins, researchers in Christopher Miller’s lab at Brandeis University in collaboration with Simon Newstead at the University of Oxford have determined the structure of one such fluoride-specific ion channel from the Bordetella pertussis bacteria called Bpe.

In a paper published by Nature on Sept. 7, lead author Randy Stockbridge, a post-doctorate fellow in Miller’s lab, and colleagues used a technique called X-ray crystallography to obtain an “atomic blueprint” illustrating the arrangement of the amino acids that make up Bpe. The details provide important insight into how Bpe exports fluoride out of the cell. Intriguingly, the schematics also point out potential weaknesses in Bpe that could be exploited to trap fluoride inside bacteria.

Based on the blueprint, the Bpe fluoride-specific ion channel resembles an hourglass and is actually composed of two Bpe protein molecules. At the center where the hourglass constricts is a sodium ion that may act like a pin that fastens the two Bpe proteins together. However, rather than having a central pore like an hourglass, the arrangement of the two Bpe molecules forms two parallel tunnels through which fluoride ions could flow. The blueprint also helps explain why Bpe only exports fluoride; the tunnels are just the right size for fluoride ions, but are too narrow for the biologically abundant chloride ion, fluoride’s larger but chemically similar cousin.

Notably, the researchers observed two unidentifiable “hazy shadows” in each tunnel, which they concluded were fluoride ions. First, many of the amino acids along the walls of each channel that protrude toward the shadows are chemically attracted to fluoride ions. Consistently, when the researchers mutated some of these amino acids to change their chemical properties, Bpe’s ability to export fluoride ions out of the bacteria was dramatically reduced. The researchers also studied the structure of a related fluoride-specific ion channel, Ec2, and found similar hazy shadows in its tunnels.

The researchers also noted a peculiar feature of Bpe that has implications for how the protein moves fluoride out. At one point in each of the tunnels, the side chain, or chemical appendage, of a particular amino acid protrudes inward, contacts the fluoride ion, and impedes its path to the exit. The side chain can swivel though, so it may be that the fluoride ion grasps it as though it were a turnstile and is then pulled to the other side when the side chain rotates.

Armed with Bpe’s blueprints, researchers can exploit structural weaknesses and develop strategies that kill bacteria by preventing fluoride from being moved out. Chemical compounds could be designed that pull the sodium ion pin and dismantle Bpe or that lock the turnstile causing a fluoride traffic jam that backs up into the cell.

In addition to Stockbridge, Miller and Newstead, the paper’s other authors are Ludmila Kolmakova-Partensky, Tania Shane, Akiko Koide and Shohei Koide.

The research was supported in part by a Wellcome Trust Investigator Award and grants from the National Institutes of Health (NIH) (RO1-GM107023 and U54-GM087519). Stockbridge also was supported by an NIH grant (K99-GM-111767). Miller is a Howard Hughes Medical Investigator.

Biophysical Society announces MPSDC Chair Eduardo Perozo as 2016 Society Fellow

On August 31, 2015 the Biophysical Society announced that MPSDC Chair Eduardo Perozo was elected as a 2016 Society Fellow. This award honors the Society’s distinguished members who have demonstrated excellence in science, contributed to the expansion of the field of biophysics, and supported the Biophysical Society. The Fellows will be honored at the Awards Ceremony during the Biophysical Society’s 60th Annual Meeting on Monday February 29, 2016 at the Los Angeles Convention Center in Los Angeles, California. Perozo was elected for his leadership and fundamental contributions in ion channel biophysics.

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