Professor Tajkhorshid Awarded Supercomputing Capacity at DOE National Laboratory
The U.S. Department of Energy Office of Science selected Professor Emad Tajkhorshid’s project for a 2015 Innovative and Novel Computational Impact on Theory and Experiment (INCITE) award. The award provides 96 million hours of massive supercomputing at a Leadership Computing Facility that focuses only on the most ambitious research projects with the potential for major breakthroughs. Tajkhorshid’s lab has been exploring the precise way in which nutrient molecules enter cells and waste molecules leave cells. Proteins known as membrane transporters undergo structural changes to allow a unidirectional transfer of molecules, functioning as active pumps, but just how the pumps work is unknown. “The Holy Grail of structural biology of membrane transporters is to describe this whole transition. Right now we only have the initial and final structures,” said Professor Tajkhorshid. Understanding the transition could allow drug developers to design more targeted drugs for major pathophysiological conditions such as psychological disorders, cancer, and multi-drug resistance. Tajkhorshid’s project, which has been developed and tested in his lab, will study the transition between structural intermediates of a number of transporters using a novel combination of several replica-based techniques coupling a massive array of all-atom molecular dynamics simulations, which are only possible with this type of supercomputing capacity. The goal of the project is to develop an atomistic view of membrane transporter transitions and to understand the ways in which the membrane transporters use energy to function as one-way pumps. The Department of Energy accords supercomputing hours to a small number of projects every year through the INCITE program, which aims to accelerate scientific discoveries and technological innovations to projects that address “grand challenges” in science and engineering. Tajkhorshid’s INCITE award is a two-year grant with the possibility of renewal, and uniquely, the award includes a staff liaison for scientific support. Dr. Tajkhorshid is a professor of biochemistry, pharmacology, and biophysics and computational biology and an affiliate of the Beckman Institute. “This award is order of magnitude larger than anything else we have had in the past. I am very pleased (actually honored) that our project was selected,” he said. To learn more about the fundamental questions involved in this research, watch Dancing Proteins: Cell Membrane Transporter Motion May Revolutionize Drug Therapies. Video courtesy of The Beckman Institute.
Read the press release from the US Department of Energy.
Posted November 19, 2014
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Professor Jongsook Kim Kemper and collaborators discover FXR and CREB as key physiological regulators of autophagy, published in the journal Nature.
Lysosomal degradation of cytoplasmic components by autophagy is essential for cellular survival and energy homeostasis under nutrient-deprived conditions. Acute regulation of autophagy by nutrient-sensing kinases, such as mTOR and AMPK, is well defined, but longer-term transcriptional regulation is not. In this study, Sunmi Seok and Ting Fu (co-first authors) in the Jongsook Kim Kemper lab in the Department of Molecular and Integrative Physiology and collaborators, including Jian Ma’s group in the Department of Bioengineering, have identified the feeding-activated nuclear receptor FXR and the fasting-activated transcriptional factor CREB as key physiological regulators of autophagy. There are several important aspects to this study. First, it was believed that autophagy occurs only under extremely stressful nutrient-deprived conditions but we show that it actually occurs physiologically during feeding/fasting. Second, autophagy does have important metabolic functions, for example lipophagy is dynamically regulated by the FXR/CREB axis. Third, this is the first report that FXR and CREB are transcriptional regulators of the autophagy gene network. Fourth, defective autophagy has been implicated in many diseases but excess autophagy is also harmful because it promotes cell death and also may provide a favorable microenvironment for tumor growth. The team's discovery that the FXR/CREB axis tightly regulates the autophagy gene network reveals potential new targets for developing new drugs to treat human diseases associated with autophagy dysfunction, including metabolic disorders, neurodegenerative disease, and cancer. This study was supported by grants from National Institutes of Health to Professor Kemper.
Scientists engineer human T cell receptors against cancer antigens
T cell receptors are found on the surface of T cells, where they bind to antigens such as those on cancer cells. After activation by the binding of the receptor, the T cell destroys the cancer cell. One of the problems associated with cancer is that a patient’s own T cells may not have the proper T cell receptors that can bind to such antigens. Over the past 15 years, the Kranz group has developed various strategies to attempt to engineer receptors that can serve these purposes, by taking a single receptor from a known T cell clone and improving its affinity for an antigen. In the present study, published in the journal Nature Communications , the scientists showed that it was possible to take a T cell receptor against one antigen (Figure) and using entirely in vitro, directed evolution techniques, to convert this receptor to a completely different specificity. The strategy could thus allow the development of specific receptors, at will, against a large array of known cancer antigens. The approach involved computational analyses to guide the design of “libraries” that contain millions of mutated T cell receptors. The mutants are each displayed on the surface of a yeast cell, and then high-speed instruments called fluorescence activated cell sorters could be used to select only those yeast cells displaying a T cell receptor that binds to the antigen of interest. In the present study, the antigen of interest was derived from human melanoma (Target B in Figure), and the original T cell receptor had been derived from a T cell clone that recognized a viral antigen (Target A in Figure). Various mutational approaches, and molecular dynamics simulations by the Tajkhorshid group, provided insight into how the specific mutations found in the selected T cell receptors allowed binding only to the melanoma antigen. A major implication of the study is that the design approach could be extended to other target antigens providing a platform to rapidly discover T cell receptors against many antigens. Current methods have required that each engineered T cell receptor be generated from human T cell clone, which can take years to produce. Engineered T cell receptors have already reached clinical trials in various therapeutic formats. The present approach provides an additional discovery strategy for their use in the treatment and detection of cancer, viral diseases, and autoimmune diseases, depending on the target antigen chosen for the specific T cell receptor.
Scientists discover a new role for estrogen in the pathology of breast cancer
Scientists have discovered a previously unknown mechanism by which estrogen prepares cells to divide, grow and, in the case of estrogen-positive breast cancers, resist cancer drugs. The researchers say the work reveals new targets for breast cancer therapy and will help doctors predict which patients need the most aggressive treatment. The University of Illinois team reports its findings in the journal Oncogene. Estrogen pre-activates the unfolded-protein response (UPR), a pathway that normally protects cells from stress, the researchers report. The UPR spurs the production of molecular chaperones that prepare cells to divide and grow. Without chaperone proteins to do the work of folding and packaging other proteins, cells – including cancer cells – cannot divide. For this reason, chaperones are a popular target for new cancer therapies. Activation of the UPR is known as a normal response to stress – when a cell lacks adequate oxygen or nutrients, for example, or is exposed to cancer-killing drugs. UPR activation prepares the cell for major changes associated with cell growth, division and survival under stress. It wasn’t known before this study, however, that estrogen initiates this pathway before such stresses appear, said University of Illinois biochemistry professor David Shapiro, who led the new analysis with lead author, M.D.-Ph.D.-student Neal Andruska. “This is a new role for estrogen in the pathology of cancer,” Shapiro said. “Others have shown that stress activates this pathway, helping to protect some tumors. What is new is our finding that estrogen can pre-activate this pathway to protect tumors.” When estrogen binds to its receptor it sparks a cascade of molecular events in the cell. A key event occurs when a channel opens in the membrane of a compartment that stockpiles calcium, and calcium floods into the cell. “That’s a signal to activate the UPR pathway, the stress pathway,” Shapiro said. “It’s also a signal that many researchers think has something to do with cell proliferation. The calcium itself may be a proliferation signal.” The stress-response pathway induces the production of chaperone proteins. “I like to think of this pathway as an assembly line,” Shapiro said. “In order for cells to divide, you’re going to have to produce a lot more proteins. The chaperones help you to package, fold up and ship all these proteins.” The UPR also is a mediator of cell death. If a normal cell is exposed to too much stress, the stress response spurs apoptosis, a kind of cellular suicide. In cancer, however, mild activation of the UPR by estrogen blunts this cell-death pathway, allowing cancer cells to survive and even resist drugs, the researchers found. The team also looked at the expression of UPR-related genes in publicly available data from samples of breast tumors obtained from women who had been diagnosed up to 15 years prior. “Andruska, who spearheaded the research and carried out the computer analysis of the breast cancer data, found that UPR activation is a very powerful prognostic marker of the course of a woman’s disease,” Shapiro said. The analysis revealed that among women with estrogen-receptor-positive breast cancer who underwent tamoxifen therapy, breast cancer was 3.7 times more likely to recur in those overexpressing the UPR. Ten years after a breast cancer diagnosis, only 15 percent of those with the highest level of UPR-gene expression were disease-free, compared with 80 percent of women with minimal UPR expression. “Our marker helps identify breast cancers that are likely to be highly aggressive and therefore require intensive therapy,” Shapiro said. U. of I. graduate student Xiaobin Zheng, postdoctoral researcher Xujuan Yang and food science and human nutrition professor William Helferich contributed to the research. The National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health funded the research. Written by: Diana Yates, News Bureau Life Sciences Editor
NSF awards BRAIN EAGER grant to team led by Martha Gillette
Gillette’s project plans to bring together neuroscientists, engineers, and chemists from across campus, to develop and use newly created, complementary technologies that will non-invasively control, measure, and analyze brain network dynamics and change in real time. Their hope is to examine how neurons in the brain are activated in response to experiences, in order to see how they cause behavioral changes and subsequent activities of the neurons, also known as brain plasticity.Gillette will work with three other faculty at the Beckman Institute: Jonathan Sweedler, professor of Chemistry, Molecular and Integrative Physiology, Neuroscience, and member in NeuroTech; Gabriel Popescu, professor of Electrical and Computer Engineering and member Bioimaging Science and Technology; and John Rogers, professor of Materials Science and Engineering and member in the 3D Micro- and Nanosystems Group. “The challenge of understanding the dynamic brain—how it remembers, enables us to move or be moved, to awake and sleep each day of our lives—lies before us. The exceptional tools we will develop under the BRAIN initiative are possible because of the science and engineering innovation and the collegial spirit at Illinois. They hold tremendous promise for identifying the signatures of neural activity that generate complex behaviors, insights not previously possible,” said Gillette. “These are truly exciting times.” Gillette’s project has an educational element: training students to merge disciplines such as neuroscience, imaging technology, engineering of new materials for electrodes, and high-resolution analysis of neuron-to-neuron signals. The project will contribute to NSF’s growing portfolio of investments in support of President Obama’s BRAIN Initiative, a multi-agency research effort that seeks to accelerate the development of new neurotechnologies that promise to help researchers answer fundamental questions about how the brain works. The EAGER grant is for $300,000 over a two-year period.
A radical reaction utilizes two of the most popular cofactors for tRNA modification
Approximately a quarter of cytoplasmic tRNAs in eukaryotic organisms contain a modified uridine at the wobble position, which plays a crucial role in maintaining the efficiency and fidelity of protein translation. The lack of this modification severely affects translation of several important proteins whose genes use biased codons that require modified tRNAs. Genetic studies indicated that the eukaryotic Elongator complex, which consists of six subunits of Elongator protein (Elp1-Elp6), performs the central step of the modification, but the mechanism was unknown. In humans, defects in the Elongator complex have been linked to several neurological diseases such as familial dysautonomia (FD), rolandic epilepsy (RE), and amyotrophic lateral sclerosis (ALS).To provide insight into the mechanism of the modification reaction carried out by the Elongator complex, Huang and coworkers first performed bioinformatic analyses and found that only Elp3 (not Elp1-2 and Elp4-6) is present in archaea, which lacks the genes responsible for a distinct tRNA modification found in bacteria. This knowledge, along with the fact that Elp3 possesses a radical SAM and a HAT domain, led the researchers to hypothesize that tRNA wobble uridine modification in archaea is similar to the one found in eukaryota, and only Elp3 is required for catalysis. This hypothesis was subsequently confirmed by their in vitro reconstitution experiment using a recombinant archaeal Elp3 protein. Huang commented that, among several interesting mechanistic details of the Elp3-catalyzed reaction revealed by additional chromatographic and spectrometric experiments, generating a radical on the methyl group of acetyl-CoA is particularly significant. Acetyl-CoA can be regarded as “the carbon currency” of living organisms, as the overwhelming majority of carbon metabolism goes through it. To their knowledge, this is the first example of a radical reaction occurring on the methyl group of acetyl-CoA, providing potentially new tools for biosynthesis/modification of natural products and macromolecules in living organisms that require formation of a carbon-carbon bond.
Biochemistry notes the passing of noted former faculty member, J. Woodland "Woody" Hastings
Read a tribute to Dr. Hasting’s life and work, published in the New York Times.
Posted August 22, 2014
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How Heat-Loving Organisms Are Helping Advance Medicine
Dr. Claudio Grosman named Romano Professorial Scholar
Dr. Claudio Grosman has been named a Richard and Margaret Romano Professorial Scholar. The three-year appointment recognizes outstanding research achievement and campus leadership through the College of Liberal Arts and Sciences. Richard and Margaret Romano have generously served and supported the University of Illinois for more than 30 years. In addition to providing annual financial support to the College of Liberal Arts and Sciences, in 2003 the Romanos created the Romano Professorial Scholar Program. This program provides significant support for the research of some of the College's most outstanding faculty members across many disciplines. Dr. Grosman is a Professor of Molecular and Integrative Physiology.
Posted August 06, 2014
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Side-chain rotamers make a difference
This influx of cations is the first step in a series of events that culminate in, for example, muscle contraction or neurotransmitter release, and its rate is tightly regulated. Indeed, naturally occurring mutations that slow down or speed up this flow of ions lead to disease.Previous mutagenesis work from the Grosman lab on the ring of glutamates in the charge-selectivity filter region of the muscle nicotinic receptor led them to propose that the rate at which ions permeate depends not only on the number of these glutamates, but also, on the conformation of their side chains. Because these inferences were made on the basis of electrophysiological observations, however, they decided to test the plausibility of these ideas using molecular simulations, thus taking advantage of the atomic detail and high temporal resolution that only these computational methods can provide. Remarkably, the simulations gave ample credence to all aspects of their proposal and allowed them to gain insight into the effect of specific glutamate rotamers on single-channel conductance.
Colin A. Wraight (1945-2014)
Professor Wraight employed biochemical and biophysical methods to understand how the structure of membrane proteins allowed them to catalyze the transfer of electrons and protons in biological energy conversion, processes fundamental to life on this planet. Born in 1945 in London, UK, he studied at the University of Bristol, earning his BSc in 1967 and his PhD in 1971. After postdoctoral research at the University of Leiden and Cornell University, and a brief faculty position at the University of California at Santa Barbara, he joined the faculty at the University of Illinois at Urbana-Champaign in 1975 as an assistant professor in the Departments of Plant Biology and Physiology & Biophysics. He held many positions during his 39 years on the faculty of our university, including serving as Director of the Center for Biophysics and Computational Biology from 1995-1999. He joined the Biochemistry Department in 1999 and served as Head of Biochemistry from 2004-2009. He also held faculty positions in the Departments of Plant Biology and Molecular & Integrative Physiology. In addition to his important research contributions, Professor Wraight was a passionate teacher and mentor, and an outstanding colleague who gave unselfishly to others. He was known for the breadth and depth of his knowledge, quick wit, and the gracious hospitality that he and his wife, Mary, extended to all. His dedication to teaching and graduate training even during his illness was an inspiration to all who knew him. He is survived by Mary and their children, Lydia, Tristan and Sebastian.
Posted July 11, 2014
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Distinguished alumnus, Phillip A. Sharp, receives honorary doctorate at convocation
May, 2014: This spring, the Department of Biochemistry and the School of Molecular and Cellular Biology recognized the accomplishments of one of our most distinguished alumni, Phillip A. Sharp, with an honorary doctorate presented at convocation.The nomination for this highest of university honors was submitted by Dr. James Morrissey, Acting Head of the Department of Biochemistry. "Professor Sharp's discoveries have fundamentally changed our understanding of gene structure and have opened new areas of research in RNA biology,” said Morrissey. “Professor Sharp also has a distinguished record of public service, and has been a steadfast friend of our department." Currently an Institute Professor with the Koch Institute for Integrative Cancer Research at MIT, Professor Sharp earned a PhD in Chemistry from the University of Illinois in 1969 and has spent the next 45 years contributing to the study of genetics and molecular biology and the development of the biotechnology industry. His remarkable scientific career led to the discovery of splicing in eukaryotes – a finding that has revolutionized the study of RNA and for which he was awarded the Nobel Prize in Physiology or Medicine in 1993. One of the founding entrepreneurs of the biotechnology industry, Professor Sharp helped start Biogen in 1978, which later merged with Idec. Now, Biogen Idec focuses on developing drugs for neurodegenerative diseases, hemophilia and autoimmune disorders. Sharp also co-founded Alnylam Pharmaceuticals in 2002 to develop RNAi as a therapeutic. Gratefully acknowledging that “somebody before me supported this University to make it possible for me to go here,” Professor Sharp and his wife, Ann, endowed a named Professorship in Biochemistry in 2006. The professorship is currently held by Dr. David Kranz, an immunologist in the Department of Biochemistry. “Having known Phil Sharp for 30 years, since the time I was a postdoctoral fellow at MIT, I have had great respect for his science and his generosity,” said Kranz. “Dr. Sharp has given time and effort to many causes, and it has been a special honor to be the inaugural holder of the Phillip A. Sharp Professorship in Biochemistry.” The University of Illinois’ School of Molecular and Cellular Biology and the Department of Biochemistry are particularly proud to recognize the many contributions and accomplishments of Dr. Sharp and honor his continued support of scientific exploration.
Posted June 30, 2014
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Microbial Diversity – A Tribute to the Life and Work of Abigail Salyers
During her 40-year career as a professor of microbiology, Abigail A. Salyers, PhD, revolutionized how we think about the bacteria that live in the human intestinal tract, made major contributions on carbohydrate metabolism and the transfer of antibiotic resistance carried on mobile elements in humans and animals and provided advice and insights on bioterrorism, transgenic plant safety, antibiotic resistance in medicine and agriculture, and more.The Department of Microbiology is hosting a special symposium in celebration of the life and work of Abigail A. Salyers. For more information about the exciting lineup of speakers and scientific program, as well as meeting registration, accommodations, and donation opportunities, please visit the symposium website. The registration deadline is Friday, October 17, 2014.
Kalsotra Awarded Nationally Competitive March of Dimes Research Grant
Assistant professor of biochemistry and medical biochemistry, Auinash Kalsotra, has been awarded the Basil O’Conner Starter Scholar Research Award from the March of Dimes. Created in 1973 and named for the first March of Dimes chairman and president, this program provides funding to young investigators to start their own research projects on topics related to the March of Dimes mission. The grant provides $150,000 over a two-year period for research on alternative splicing’s role in Myotonic Dystrophy, a multi-systemic disease that affects about 1 in 8000 people.
Alternative splicing is a key mechanism that produces precise assortment of proteins for each cell type. It is a highly regulated process, which when gone awry results in diseases like myotonic dystrophy type 1 (DM1). DM1 arises due to an unusual mutation where a small DNA segment of the mutated gene is repeated hundreds of times. When the mutated gene is copied into RNA, it gets trapped inside the nucleus and becomes toxic by disrupting function of muscleblind like (Mbnl) family of splicing regulatory factors. Mbnl proteins normally participate in regulation of developmental splicing transitions. Their inactivation in DM1 results in expression of embryonic splicing patterns, which is detrimental to the function of adult tissues.
While the role of Mbnl1 in DM1 skeletal and cardiac muscle pathology is clear, the effects of its loss of activity in the gastro-intestinal and other tissues are poorly understood. Dr. Kalsotra's project aims to characterize Mbnl1 function in the liver by identifying its RNA targets and determining the consequences of its loss on liver physiology and function. These studies will advance our understanding of Mbnl1 function in liver development and provide new insights into DM1 pathophysiology.
The mission of the March of Dimes is to promote healthy pregnancies and to support research that can lead to the prevention of birth defects. Dr. Kalsotra’s research will lead to our understanding of molecular mechanisms that may be responsible for the developmental defects observed in this debilitating disease. Dr. Kalsotra holds appointments in both the College of Medicine and the School of Molecular and Cellular Biology at the University of Illinois at Urbana-Champaign.
Posted February 19, 2014
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MicroRNA misregulation in muscular dystrophy
Assistant Professor of Biochemistry, Auinash Kalsotra, and colleagues have discovered the process by which myotonic dystrophy affects activity of the small bits of genetic material called microRNAs in the heart. Cardiovascular dysfunctions are the second leading cause of death in people with this particular type of muscular dystrophy. Their findings were published in the journal Cell Reports on January 9, 2014.
According to Dr. Kalsotra, myotonic dystrophy is a multi-systemic disease that affects about 1 in 8000 people. It occurs because of a change in a gene that is important for muscles. (Specifically, it is a trinucleotide repeat expansion in the dystrophia myotonica-protein kinase gene.) While most myotonic dystrophy research has focused on problems related to types of messenger RNAs produced from our genes by altered RNA splicing, this study demonstrates additional problems with expression of a class of regulatory RNAs known as microRNAs.
Dr. Kalsotra has appointments in both the College of Medicine and the School of Molecular and Cellular Biology at the University of Illinois at Urbana-Champaign.