Ion channels, transporters, and lipid scramblases are integral membrane proteins that play vital roles in enabling the movement of ions, nutrients, and lipids across biological membranes. We use a combination of biophysical, structural, and bioinformatic approaches to elucidate the structural and mechanistic underpinnings of ion and lipid transport. We focus on two membrane protein families, the CLC channels and transporters and the TMEM16 channels and scramblases.
We are interested in understanding the molecular, cellular, and circuit mechanisms that give rise to the rich neural dynamics observed in the brain. Neural dynamics, the ongoing time‐varying activity patterns in populations of neurons, are critical for a wide range of motor and cognitive behaviors. To understand neural dynamics, we work at the interface between biology and physics, applying in awake animals an approach that combines molecular‐genetic manipulations, multi‐photon microscopy for stimulating and monitoring networks at the single-cell level, electrophysiology, statistical and machine learning, computational modeling, and control theory. Our efforts not only yield basic science insights into neuronal computations and how neurons interact to generate global function, but also help outline therapeutic strategies for dealing with disorders of neural dynamics.
How does the surrounding bilayer modulate channel function? The modulation results, at least in part, from alterations in the bilayer's mechanical properties, providing a novel mechanism for controlling membrane protein function. We have developed methods to measure the changes in bilayer mechanics, which are used to relate changes in membrane structure to changes in channel function.
We are interested in how molecular motions underly function in ion-driven membrane transporters. We employ crystallography and cryo-EM to determine transporters’ structures, single-molecule fluorescence microscopy and NMR to probe their dynamics, and bioinformatics to explore evolution. We are especially interested in transporters involved in synaptic signaling. We apply our mechanistic understanding to develop pharmacological strategies to modulate transporter activity in disease states.
The Burré laboratory is interested in understanding pathogenic events at the neuronal synapse that trigger neurological disorders, and to identify strategies to overcome identified deficits. Much evidence points to presynaptic terminals as initiation site for neurological diseases, where synaptic dysfunction has been shown to precede neuron death and to occur long before neuropathological symptoms become apparent. Yet, virtually nothing is known about processes involved. We currently focus on synucleins in Parkinson’s disease and other synucleinopathies, and on Munc18-1/STXBP1 and SNAP-25 in neurodevelopmental diseases including epilepsy. We employ an array of cutting-edge technologies, including biophysics, biochemistry, cell biology, imaging, and mouse models of neuropathology.
Our lab uses computation and experiments to develop quantitative, multiscale models of the effects of small molecules on biomolecular macromolecules and cellular pathways. We utilize physical models and rigorous statistical mechanics to engineer novel therapeutics and tools for chemical biology and understand the physical driving forces behind the evolution of resistance mutations. We apply advanced algorithms for molecular dynamics simulations on GPUs and distributed computing platforms, in addition to robot-driven high-throughput experiments characterizing biophysical interactions between proteins and small molecules.
Our lab is interested in synaptic function at the molecular and circuit levels. Formation and proper function of the nervous system depend critically on the operation of chemical synapses, which are the means by which neurons transmit information to one another. We study the molecules that underlie synaptic vesicle fusion and endocytosis in C. elegans using optical, genetic, biochemical, and behavioral approaches. We are currently focused on three lines of research: spatial and temporal dynamics of synaptic proteins, the mechanisms underlying synaptic vesicle fusion and its modulation, and the impact of axonal ER on synapse function, axon integrity, and neurodegeneration.
My lab is primarily involved with the application of NMR spectroscopy to problems in non-native structural biology. This includes characterizing the location and extent of structure in and the intermolecular interactions of aggregation-competent partially unfolded states of proteins involved in neurodegenerative disease. Specific targets include Alzheimer's Disease and Parkinson's Disease related proteins. We are also pursuing structural characterization of lipid-induced conformational changes of these proteins.
Our research group is focused upon determining the mechanisms of intracellular ion transport with a particular focus upon the lysosome. We use a variety of structural and biophysical tools including cryo-electron microscopy, X-ray crystallography and electrophysiology to characterize these channels.
One of our research projects focuses on the structural biology of the mechanisms of activation of G-proteins by G-protein-coupled receptors (GPCRs). The signaling from GPCRs to G-proteins is one of the main signaling systems used in biology. Although we have an outline of this signaling system, the molecular bases for many steps in this signaling cascade are poorly understood. One of the pressing issues is how GPCRs activate G-proteins. Currently we use the cryo-electron microscopy, cellular and biochemical approaches to address this question.
Our overall goal of is to uncover dynamic mechanisms in fundamental biological processes of signal transduction by cell surface proteins, including G protein-coupled receptors (GPCRs), neurotransmitter:sodium-symporters, major facilitator superfamily transporters, and lipid scramblases. We use advanced quantitative methods of theoretical and computational biophysics, developed and utilized at the highest level of each specialty. We pursue interdisciplinary and multi-scale strategies integrating biophysical theory and computation with biophysical measurements and molecular cell biology experimentation.
Membrane signaling proteins provide the molecular basis for many neurological functions and the pathophysiology of many neurological and neuropsychiatric diseases. Our lab uses high-resolution optical and chemical methods, including the development of chemical optogenetic tools and single-molecule fluorescence-based assays, to elucidate the fundamental biophysical processes that drive receptor function. We aim to gain a deeper understanding of the role of individual receptors and downstream effectors in synapse function and disease.
We are a basic research laboratory that studies the structural, biochemical, and functional basis for macromolecules involved in post-translational protein modification by ubiquitin and ubiquitin-like proteins including SUMO, and pathways that contribute to co- and post-transcriptional RNA maturation, processing and decay.
Our laboratory uses a combination of cryo-electron microscopy, x-ray crystallography, and functional approaches to study the mechanisms of eukaryotic ion channels involved in calcium signaling and membrane-embedded enzymes.
The central focus of the laboratory is the development and use of new optical microscopy and biophysical techniques to study the properties of living cells. We use digital imaging devices, confocal microscopes, multiphoton microscopy, automated microscopy systems, and image processing computers to analyze processes occurring at specific sites within cells. Using these tools, we study the distribution and movement of various types of molecules in cells. We are interested both in the basic mechanisms regulating the movement of molecules through cells as well as the role that these processes play in specific diseases.
The research in our lab addresses questions of molecular structure and transmembrane signaling mechanisms. In particular, the lab is focused on ion channel structural dynamics and function. We make extensive use of high-resolution single-particle cryo-EM and sub-tomogram averaging, along with an array of biochemical and biophysical methods. Additionally, the lab is interested in using cutting-edge correlative tomographic imaging approaches to address frontier questions of 3D molecular organization, structure, and mechanism in situ.
We are interested in fundamental aspects of cellular membrane biogenesis. Our work covers a number of areas concerned with lipid biosynthesis, propagation of the phospholipid bilayer of biological membranes, translocation (flip-flop) of lipids across bilayers, and intracellular lipid transport. We approach these problems through biochemical, biophysical, genetic and chemical methods.
We are interested in understanding how receptors located on the surface of developing axons and neurons interact with extracellular ligands to guide the development of the nervous system and the wiring of the brain. In our investigations, we use X-ray crystallography combined with other biophysical, biochemical, and cell biological approaches. Some of the ligand/receptor signaling systems that we currently study include ephrins/Eph receptors, netrins/DCC/Unc5, NogoR/Nogo and angiopoietins/Ties. Recently we also became interested in how henipaviruses interact and fuse with target cells.
Research in our laboratory is geared toward understanding how ion channel protein structure and mechanism interrelate at the molecular level to allow channels to elaborate various biological properties. We use a combination of structural, biochemical, and electrophysiological approaches to evaluate fundamental channel properties.
The kidney precisely controls the levels of electrolytes in the plasma. This function is vital, as the body requires a constant internal milieu to function properly. Our laboratory is interested in the cellular and molecular events involved in the transport of Na+ and K+ between blood and urine, and in the hormonal mechanisms underlying the regulation of these transport processes.
Our research group is interested in the structural biology of pathways that are altered in cancer, with particular emphasis on pathways that control the growth and proliferation of the cell. In cancer, mutations and other alterations in these pathways lead to the uncoupling of cell growth from growth-regulatory signals and contribute to the unrestricted proliferation of the tumor cell.
Our mission is to develop a “new” generation of optical imaging technologies. We aim to analyze macromolecular interactions and motions at the nanometer scale in vivo and to study the three-dimensional architecture of complex molecular machines and subcellular ultrastructures in situ. We also refine and apply ultrahigh-resolution spectroscopy techniques to dissect multistep complex biochemical processes using in vitro reconstituted single-molecule assays.
Our lab focuses on diseases caused by abnormal function of ion channels, specialized proteins in cells that control electrical activity. The lab applies electrophysiology, biochemistry, structural biology, and animal models of human diseases to discern how aberrant ion channel function leads to diseases such as cardiac arrhythmias, neuropsychiatric disorders, ataxias, and epilepsy. Recent work has elucidated novel roles for voltage-gated ion channels in non-excitable tissue and during embryonic development.
My lab conducts high-resolution, single-molecule studies of the molecular mechanisms of ribosome functions and gene expression control.
We are interested in the mechanism of chromosome replication, a process that is highly conserved across eukaryotes and that involves the duplication of both the chromosomal DNA and its associated chromatin states. As chromosomes are the carriers of both the genetic and epigenetic information, faithful chromosome replication is of fundamental importance for genome maintenance during normal cell proliferation. Conversely, defects in chromosome replication are a major driver of the genomic instability observed in cancer cells. To understand the molecular mechanisms by which eukaryotic cells carry out and monitor accurate genome replication we employ a fully reconstituted DNA replication system based on purified proteins from the budding yeast, S. cerevisiae. Research projects are focused on the mechanistic characterization of the core DNA replication machinery, replication-coupled chromatin assembly, DNA replication stress, and S phase checkpoints.
My current studies are focused on the role of the lipid bilayer in drug-induced regulation of membrane proteins and teasing apart this general mechanism from direct drug binding. To answer these questions I developed a fluorescence-based stopped-flow assay to monitor changes in the function of KcsA, a prototypical prokaryotic potassium channel, in various well defined lipid environments. These studies will elucidate the role of cell membrane in the membrane protein regulation by lipophilic drugs and thereby provide insight into the mechanism/s underlying multi- and off-target effects of lipophilic drugs.
The focus of Ryan's lab is on the molecular basis of synaptic transmission in the mammalian brain. We want to understand the regulation of vesicle traffic in presynaptic terminals and how it impacts function and dysfunction. We use biophysical tools to characterize the molecular machinery in living synapses. We use many types of optical assays in combination with molecular, genetic, and chemical tools. In recent years we have also been addressing how endocytosis is regulated at nerve terminals and how vesicles are clustered and mobilized for secretion upon action potential firing.
We perform atomic force microscopy (AFM)-based research of biological samples, with a particular interest in membrane phenomena. Our data reports about the structure, dynamics, diffusion, interaction, mechanics and supramolecular assembly of membrane proteins (channels, transporter and membrane trafficking proteins) and other membrane constituents. The Scheuring Lab offers a truly interdisciplinary environment, where students and postdocs work in fields ranging from membrane protein expression and purification to technical developments making AFM faster and more sensitive.
The goal of my research is to understand the mechanisms and structures of enzymes that perform and regulate essential nucleic acid transactions. My research integrates diverse experimental approaches (including virology, biochemistry, structural biology, and genetics) and applies them to model systems ranging from viruses to bacteria to fungi to mammalian cells. An explicit aim is to identify novel enzymatic targets for treatment of human diseases.
We study mechanisms of membrane-associated macromolecular machines (MAMMs) in cell physiology with methods of molecular and computational biophysics, bioinformatics, and mathematical modeling. New methodological developments for performance and analysis of large-scale computational molecular dynamics simulations are used to learn the underlying structural and dynamic mechanisms of the molecular systems involved in neurotransmission, drug abuse mechanisms, cancer, and currently the Covid-19 virus. In synergistic collaborative studies with experimental labs, we investigate functional mechanisms, allostery, membrane involvement and the design of function-modifying ligands for the MAMMs, including GPCRs, transporters, and TMEM16 membrane lipid scramblases, as well as processes of viral infectivity.