Chairs
Professor George Lorimer FRS, University of Maryland, USA
Professor George Lorimer FRS, University of Maryland, USA
George Lorimer has been Professor of Biochemistry at the University of Maryland since 1997. In 1978 he joined the Central R&D department of the Du Pont Company. While there, he first worked on the mechanism of Rubisco, the enzyme that fixes CO2 in photosynthesis. He was elected a Fellow of the Royal Society in 1986 for his work on Rubisco. In 1989, using an unequivocally unfolded protein and the purified chaperonin proteins GroEL and GroES, his group was the first to demonstrate the ATP-dependent folding of Rubisco and many other proteins. In 1997, he was elected to the National Academy of Sciences for his work on chaperonin-assisted protein folding. George has since shown that GroEL can perform work on substrate protein during allosteric transitions. He has determined the crystal structure of the functional form, the symmetric GroEL:GroES2 ‘football’ and established that the GroEL rings operate as parallel-processing, iterative annealing molecular machines.
09:05-09:30
The nicotinic acetylcholine receptor a typical model of allosteric membrane protein
Professor Jean-Pierre Changeux, Collège de France and Institut Pasteur, France
Abstract
The concept of allosteric interaction (1) which was initially proposed to account for the inhibitory feedback mechanism mediated by bacterial regulatory enzymes contrasts with the classical mechanism of competitive, steric, interaction between ligands for a common site. Accordingly allosteric interactions are indirect interactions that take place between topographically distinct sites and are mediated by a discrete & reversible conformational change of the protein.
The concept was soon extended to membrane receptors for neurotransmitters (2) which behave as «molecular switches» mediating the signal tranduction process at the synapse, which, in the case of the acetylcholine nicotinic receptor (nAChR), links the ACh binding site to the ion channel (3). Furthermore, pharmacological effectors, referred to as allosteric modulators, such as Ca++ ions and ivermectin, were discovered that enhance the transduction process when they bind to sites distinct from the orthosteric ACh site and the ion channel on the nAChR (4). The recent X-ray structures, at atomic resolution, of the resting & active conformations of prokaryotic and eukaryotic homologs of the nAChR, in combination with atomistic molecular dynamics simulations (5) reveal a stepwise quaternary transitions in the transduction process with tertiary changes which modify the boundaries between subunits. These interfaces host orthosteric and allosteric modulatory sites which structural organization changes in the course of the transition. The model emerging from these studies has lead to the conception and development of new pharmacological agents. For example, looking for chemical therapies against Autism, a strategy was elaborated on the basis of brain genes expression data, using the concept of coherent-gene groups controlled by transcription factors (TFs), which resulted in the design of allosteric modulators targeted toward specific TFs expressed at critical steps of brain development (6).
1. Changeux JP (1961) The feedback control mechanisms of biosynthetic L- threonine deaminase by L-isoleucine. Cold Spring Harb Symp Quant Biol 26:313–318 ; Gerhart JC, Pardee AB (1962] The enzymology of control by feedback inhibition. J Biol Chem 237:891–896
2. Changeux (1964) PhD Thesis ; (1965) [On the allosteric properties of biosynthesized l-threonine deaminase. VI. General discussion]. Bull Soc Chim Biol (Paris) 47:281-300.
3. Taly A, Corringer PJ, Guedin D, Lestage P, Changeux JP. (2009) Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system Nat Rev Drug Discov. 8:733-50.
4. Corringer, P.J., Poitevin, F., Prevost, M.S., Sauguet, L., Delarue, M., Changeux, J.P.(2012) Structure and pharmacology of pentameric receptor-channels: from bacteria to brain. Structure 20, 941–956
5. Changeux JP (2014) Protein dynamics and the allosteric transitions of pentameric receptor channels. Biophys Rev. 6:311-321 ; Cecchini M, Changeux JP (2014) The nicotinic acetylcholine receptor and its prokaryotic homologues: Structure, conformational transitions & allosteric modulation. Neuropharmacology Dec 18. pii: S0028-3908(14)00450-X. doi: 10.1016/j.neuropharm.2014.12.006
6. Tsigelny IF, Kouznetsova VL, Baitaluk M, Changeux JP.(2013) A hierarchical coherent-gene-group model for brain development. Genes Brain Behav. 12:147-65.
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Professor Jean-Pierre Changeux, Collège de France and Institut Pasteur, France
Professor Jean-Pierre Changeux, Collège de France and Institut Pasteur, France
Jean-Pierre Changeux PhD is International Faculty at the Kavli Institute for Brain and Mind University of California San Diego and Honorary Professor at the Collège de France and Institut Pasteur, Paris.
Changeux PhD studies led to the discovery that chemical signals regulate the biological activity of proteins by acting at ‘allosteric’ sites distinct from the biologically active sites via a conformational change (1961-1965). He then proposed (1964,1966) that this type of regulation applies to receptor mechanisms engaged in the transmission of chemical signals in the nervous system and through his life-time work, validated this insight. His studies were initiated by the first identification of a neurotransmitter receptor: the nicotinic acetylcholine receptor together with Lee and Kasai (1970) and culminated by a contribution, with Corringer and Delarue to establishing the 3D structure and conformational transition of prokaryotic orthologs of nicotinic receptors by X-ray crystallography and molecular dynamics (2005-15). Changeux and his colleagues also deciphered the topology of allosteric modulatory sites for pharmacological ligands (1996-2011), thereby substantiating a novel strategy of drug design based on allosteric modulation.
Moving to neuronal networks, Changeux, together with Courrège and Danchin (1973, 1976) formulated and experimentally tested the theory that long-term epigenesis of neuronal networks occurs by the activity-dependant selective stabilisation and elimination of developing synapses.
Last, in particular with Dehaene, he proposed and tested models for defined cognitive tasks and their pharmacological modulation (1991-2015) in particular, a neuronal hypothesis for conscious processing, implicating a ‘global neuronal workspace’ composed of a brain-scale horizontal network of long axon neurons (1998-2015).
Changeux has published several books including Neuronal Man (1985), What Makes Us Think? (with Paul Ricoeur) (2002), Physiology of truth (2002).
His academic accolades include the Gairdner award (1978), the Wolf prize (1983), Médaille d'Or, Centre National de la Recherche Scientifique, Paris, (1992), the Goodman and Gilman Award in drug receptor pharmacology (1994), the Balzan Prize (2001), the US National Academy of Sciences Award in Neurosciences (2007), the Japanese Society for the Promotion of Science Award for Eminent Scientists,Tokyo (2012) and the Olav Thon prize Oslo (2016).
09:40-10:05
Genetically tunable frustration controls allostery in an intrinsically disordered transcription factor
Professor Vincent J. Hilser, Johns Hopkins University, USA
Abstract
Intrinsically disordered proteins (IDPs) present a functional paradox because they lack stable tertiary structure, but nonetheless play a central role in signaling, utilizing a process known as allostery. Historically, allostery in structured proteins has been interpreted in terms of propagated structural changes that are induced by effector binding. Thus, it is not clear how IDPs, lacking such well-defined structures, can allosterically affect function. Here we show a mechanism by which an IDP can allosterically control function by simultaneously tuning transcriptional activation and repression, using a novel strategy that relies on the principle of energetic ‘frustration’. We demonstrate that human glucocorticoid receptor tunes this signaling in vivo by producing translational isoforms differing only in the length of the disordered region, which modulates the degree of frustration. We expect this frustration-based model of allostery will prove to be generally important in explaining signaling in other IDPs.
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Professor Vincent J. Hilser, Johns Hopkins University, USA
Professor Vincent J. Hilser, Johns Hopkins University, USA
Vincent J. Hilser has earned a BS degree in chemistry from St. John’s University (1987), and a PhD in Biochemistry from Johns Hopkins University (1995). From 1995 through 1997, he performed postdoctoral research in the lab of Ernesto Freire (John Hopkins University). In 1997, he accepted a position as an Assistant Professor in the Sealy Center for Structural Biology at the University of Texas Medical Branch in Galveston, Texas, ultimately rising to the rank of Professor and Director of the Center from 2005-2010. In 2010, he accepted a position in the Department of Biology at Johns Hopkins University, and has served as Chair of Biology since 2014. Dr Hilser’s research focuses on understanding the physical and energetic basis, as well as the functional consequences, of conformational heterogeneity in proteins and applying this understanding to the development of novel fold classification and protein design strategies and investigations into allosteric mechanism.
10:35-11:05
New approaches for elucidating allosteric mechanisms and their application to chaperonins
Professor Amnon Horovitz, Weizmann Institute of Science, Israel
Abstract
Chaperonins are allosteric machines that consist of two back-to-back stacked heptameric rings with a cavity at each end where protein folding can take place. They assist protein folding by undergoing large conformational changes that are controlled by ATP binding and hydrolysis. The concerted Monod–Wyman–Changeux and sequential Koshland–Némethy–Filmer models of cooperativity are often used to describe such allosteric switching. In general, however, it has been impossible to distinguish between these different allosteric models using ensemble measurements of ligand binding in bulk protein solutions. In this talk, two approaches that break this impasse will be described: one that is kinetic and a second that is based on native mass spectrometry. Using these approaches, it was possible to show that the chaperonin GroEL from E. coli undergoes concerted intra-ring conformational changes whereas its eukaryotic homologue CCT/TRiC undergoes sequential intra-ring conformational changes. The impact of these different allosteric mechanisms on the folding functions of GroEL and CCT/TRiC will be discussed.
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Professor Amnon Horovitz, Weizmann Institute of Science, Israel
Professor Amnon Horovitz, Weizmann Institute of Science, Israel
Amnon Horovitz completed his undergraduate and graduate studies in biochemistry at the Hebrew University of Jerusalem. His thesis work on ‘Additivity in the effects of amino acid substitutions on protein-protein interactions’ was carried out under the supervision of Professors M. Rigbi and R. D. Levine. In 1989, he joined the laboratory of Professor Alan Fersht in Cambridge, England as a post-doctoral fellow where he worked on developing the double-mutant cycle method and applying it to study protein folding and stability. In 1991, he joined the faculty of the Department of Structural Biology at the Weizmann Institute of Science in Israel where he has been since. Amnon Horovitz was chair of the Department of Structural Biology from 2000 to 2006 and has been Full Professor since 2004. He has won several awards including the Hestrin Prize of the Israel Biochemical Society (1989) and the Zimmer Award of the University of Cincinnati (2008). He is currently President of the Israel Society for Biochemistry and Molecular Biology.
11:15-11:45
Cooperative Dynamics of Neurotransmitter Transporters: Learning from Experiments and Computations
Professor Ivet Bahar, University of Pittsburgh, USA
Abstract
Recent years have seen a breakthrough in the elucidation of the structure and dynamics of sodium-coupled neurotransmitter transporters. These membrane proteins are essential regulators of neurotransmission in the brain, and their malfunction is implicated in several neurological disorders. We have now made significant progress in understanding the complex machinery of these secondary transporters, the way they undergo cooperative structural changes between outward-facing and inward-facing states for transporting their substrate and sodium ions, while they also permit for chloride channeling. We will present recent progress made in the elucidation of the mechanism of function of two major groups of transporters and their alteration by ligand binding and/or multimerization: Glutamate transporters, exemplified by the archaeal transporter GltPh which served as a useful model for understanding the dynamics of excitatory amino acid transporters (EAATs); and dopamine transporters as an important member of transporters sharing the LeuT fold. We will show how the multidomain structure or multimerization properties are essential to altering not only their conformational dynamics, but also the coupled membrane remodeling in the synapse, based on recent progresses made in both visualizing and modeling the molecular-to-cellular dynamics of these important transporters that regulate glutamatergic and dopaminergic signaling in the central nervous system.
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Professor Ivet Bahar, University of Pittsburgh, USA
Professor Ivet Bahar, University of Pittsburgh, USA
Ivet Bahar works at the interface between computational and life sciences, developing models and methods rooted in fundamental principles of physical sciences and engineering. She is specialised in biomolecular systems dynamics and developed several tools to facilitate the evaluation of collective dynamics for biomolecular systems. She is a Distinguished Professor in the Department of Computational & Systems Biology at the University of Pittsburgh, School of Medicine. She co-founded the Joint PhD Program in Computational Biology between the University of Pittsburgh and Carnegie Mellon University. She is a member of the European Molecular Biology Organization (EMBO).
11:55-12:25
Kinetics and thermodynamics of protein assembly
Professor Birgit Strodel, Jülich Research Centre, Germany
Abstract
The aim of my work is to understand the physicochemical principles that govern the highly complex process of protein assembly. This process may lead to fatal diseases, as in the case of Alzheimer's disease, but life also profits from it as many molecular processes within a cell are carried out by molecular machines that are built from a large number of proteins. All-atom molecular dynamics (MD) simulations of protein assembly in explicit solvent have been performed for over a decade, revealing valuable information about this phenomenon. The focus of my work lies on the analysis of MD simulations to elucidate the kinetics and thermodynamics of protein assembly processes. To this end, we developed kinetic transition networks showing the transitions between aggregates of different sizes and structural characteristics, allowing us to extract both the thermodynamics and kinetics of the assembly process. While the kinetic transition networks are based on conformational clustering, Markov state models (MSMs) use kinetic clustering for the identification of metastable states. The application of MSMs to protein assembly is highly desirable but challenging, as I will demonstrate in this talk for the aggregation of a small peptide. I will conclude my talk with a perspective on how the methods developed in my group can be applied to molecular machines in order to identify structural changes and kinetically relevant intermediates in their functional cycle.
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Professor Birgit Strodel, Jülich Research Centre, Germany
Professor Birgit Strodel, Jülich Research Centre, Germany
Birgit Strodel studied Chemistry at the universities of Düsseldorf (Germany) and North Carolina, Chapel Hill (USA). She received her PhD in Theoretical Chemistry from the University of Frankfurt/Main (Germany) in 2005 under the supervision of Professor Gerhard Stock. She then spent 2006–2008 as a post-doctoral research associate at the Chemistry Department at the University of Cambridge (UK), working with Professor David J. Wales. Since 2009 she had been head of the Computational Biochemistry Group at the Jülich Research Centre. In addition, she was appointed to a Professorship at Heinrich Heine University Düsseldorf in 2011. Her research primarily involves the study of protein-protein interactions and protein aggregation, for which she develops and applies simulation techniques to reveal the thermodynamics and kinetics of such processes.