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Departments: Protein-Glycoconjugate Interactions

Gerald Hart

jennbryant on July 20, 2021

Gerald Warren Hart, Ph.D.

October 1st, 2018, Hart moved to take a position as the Georgia Research Alliance William Henry Terry, Sr. Eminent Scholar in Drug Discovery, and Professor of Biochemistry and Molecular Biology at the Complex Carbohydrate Research Center, University of Georgia. Prior to that appointment, he worked at Johns Hopkins Medical School for 41 years.  He has served as the Director of Biological Chemistry at JHU SOM for over 20 years. Hart was elected as a Fellow of ASBMB in 2022 and the President of ASBMB (2018-2020). Hart received the 2019 President’s Innovator Award from the Society for Glycobiology (SFG), the  2018 Herb Tabor Award from ASBMB, the 2018 Yamakawa award from the Japan Consortium for Glycobiology and Glycotechnology, the Karl Meyer Award from SFG in 2006, and the first IGO Award from the International Glycoconjugate Organization in 1997. He was an Associate Editor of the Journal of Biological Chemistry (2012-2022) and of Molecular and Cellular Proteomics (currently). He also founded the journal Glycobiology in 1989, now the leading journal in the field and served as its Editor-In-Chief for 12 years. During his graduate career, he performed some of the earliest studies on cell surface heparan sulfates and on the roles of proteoglycans and sulfotransferases in corneal transparency. During his postdoctoral work, he determined the minimal sequence requirement for N-glycosylation (-Asn-X-Ser-) and showed that corneal keratan sulfate is made via the N-glycan biosynthetic pathway. In 1983, Hart’s laboratory discovered O-GlcNAcylation, he co-led elucidation of GPI anchor biosynthesis with Paul Englund’s group, and his lab documented the importance of protein structure for N-glycosylation. His lab later discovered the extensive crosstalk between O-GlcNAc and phosphorylation, which regulates transcription and signaling and underlies the etiology of diabetes, neurodegenerative disease, cardiovascular disease and cancer. ~319 publications; Google H-factor = 129; i10-index=284.

Robert J Woods

jennbryant on July 12, 2021

Short Biography:
Dr. Woods received both his B.Sc.(Honors) in engineering chemistry in 1985 and his Ph.D. in 1990 in computational and synthetic organic chemistry from Queen’s University in Kingston, Ontario, Canada. He joined the CCRC in January 1995. Dr. Woods is a senior investigator on a technological research and development project of the National Institutes of Health Resource Center for Biomedical Complex Carbohydrates. He has been invited to write an entry on carbohydrate force fields for the Encyclopedia of Computational Chemistry. He is a member of UGA’s Campus Information Technology Forum and the UGA Modeling Laboratory Operations Committee, and has made recent presentations at the International Carbohydrate Symposium, the Gordon Research Conferences, and the National Research Council of Canada. Full publications: 33.

Research Interests:
Dr. Woods’s research examines the relationships between the conformations of carbohydrate molecules and biological recognition and activity, particularly the mechanisms involved in carbohydrate recognition in immunological events. Significant alterations in the biological activities of peptides and proteins often accompany the covalent attachment of an oligosaccharide (glycosylation) to one or more of their amino acid residues. Approximately 60% of all mammalian proteins are glycosylated, and the glycoproteins that are generated by glycosylation are also frequently found attached to the cell surfaces of bacteria, fungi, and parasites.
But the roles of oligosaccharide moieties are extremely diverse. In mucins, for example, the carbohydrate component of a glycoprotein may be present in a largely structural capacity, whereas in human chorionic gonadotropin or tissue plasminogen activator it alters the functioning of the protein. The carbohydrate component may also be the part of the glycoprotein recognized by the immune system, directly affecting antibody-antigen interactions, self- and non-self-recognition, and auto-immune disorders. Recognition by the host’s immune system of the carbohydrate portion of the glycoproteins of these pathogenic microorganisms is essential for an immune response to be generated by the host. Moreover, an understanding of the factors that enable antibodies to distinguish among glycoproteins is essential to the rational development of vaccines. Elucidating the conformational properties of glycoproteins and their carbohydrate components is key to this understanding. Dr. Woods’s investigations seek to define the conformational properties of the free oligosaccharides of such glycoproteins, the effect of attachment of the oligosaccharide to the protein, and the mechanisms of non-covalent oligosaccharide-protein interactions.

Traditional experimental techniques that have been successfully applied to proteins have not been able to determine conclusively the conformational properties of glycoproteins. The conformation of an oligosaccharide in aqueous solution is determined by interactions (both steric and electronic and between both attached and nonbonded atoms) between the sugar residues and between these residues and solvent molecules. All these interatomic interactions must be adequately described in order to arrive at an accurate prediction of an oligosaccharide’s conformational preferences. Moreover, the structure may need to be described as an ensemble of conformations rather than as a single conformation, accounting for both spatial and temporal properties of the oligosaccharide. Mathematically, such a description can be obtained by applying a molecular mechanical force field in molecular dynamics (MD) simulations, a standard technique in the analysis of protein and oligonucleotide structures.

Dr. Woods’s group utilizes, in conjunction with experimental methods (e.g., 2D 1H-NMR spectroscopy), the computational techniques of molecular dynamics (MD) and free energy perturbation simulations to elucidate the conformational properties of oligosaccharides. Simulations are in no way constrained to reproduce the experimental data. The computational simulations use the all-atom AMBER force field for proteins and nucleic acids and a novel set of parameters developed by Dr. Woods’s group for use with carbohydrates, GLYCAM. The GLYCAM parameters make it possible to probe the interatomic interactions responsible for oligosaccharide and glycoprotein dynamics and compare these directly with experimental NMR data that are often consistent with numerous possible conformations. These parameters are currently suitable for all biologically relevant N- and O-linkages in oligo- and polysaccharides and glycoproteins.

Current research projects using these techniques include examinations of bacterial antigen-antibody interactions, as well as carbohydrate-lectin interactions. Carbohydrate antigens associated with Salmonella paratyphi B and group B Streptococcus are being studied to understand the energetic contributions hydrophobic and hydrophilic interactions make to antibody binding energy. More applied aspects of the research include the screening of synthetic combinatorial peptide libraries for peptides that bind to carbohydrate receptor proteins (antibodies and lectins) and their subsequent co-crystallization with the receptor. Peptides are characteristically more antigenic than carbohydrates, and the Woods laboratory’s interest in carbohydrate mimics is driven by a desire to produce non-carbohydrate molecules that can either act as anti-bacterial vaccines or inhibit auto-immune reactions.

Dr. Woods’s research is supported by the National Institutes of Health and the National Science Foundation.

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Lance Wells

jennbryant on July 12, 2021

Short Biography:
Dr. Wells received his B.S. in Chemistry, with a minor in Psychology, in 1991 from the Georgia Institute of Technology, and after spending two years working at the Microchemical Facility, his Ph.D. in Biochemistry and Molecular Biology in 1998 from the Emory University School of Medicine. A postdoctoral research fellowship at the Johns Hopkins School of Medicine in Biological Chemistry followed, which was supported by a National Research Service Award from the National Cancer Institute of the NIH. Dr. Wells joined the CCRC in August of 2003. Full publications: 98.

Research Interests:
Using a combination of methodologies, including mass spectrometry, protein biochemistry, cell biology, genetics, proteomics, and molecular biology, we study the role of PTMs (primarily O-glycosylation) in a variety of pathophysiological processes including cancer, diabetes, viral infection, neurological disorders, and congenital muscular dystrophy. Our research is aimed at increasing our understanding of how increased functional diversity leads to finer control of biological processes. The hope is that by understanding the role of PTMs, we will not only more accurately describe fundamental biological processes but will also elucidate novel therapeutic targets in disease states where these processes have become dysregulated.

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Michael Tiemeyer

jennbryant on July 12, 2021

Short Biography:
Dr. Tiemeyer received his B.A. in biology in 1982 and his Ph.D. in neuroscience in 1989 from The Johns Hopkins University. He was a Helen Hay Whitney postdoctoral fellow in developmental neurobiology at the University of California at Berkeley. Prior to joining the CCRC faculty, Dr. Tiemeyer was a faculty member in cell biology at Yale University School of Medicine and Director of Biochemical and Clinical Analytics and New Methods Development at Glyko/Biomarin, Inc. Full publications: 27.

Research Interests:
The surfaces of all eukaryotic cells are richly endowed with a diverse array of complex glycoconjugates. Therefore, carbohydrate moieties linked to protein, lipid, and glycosaminoglycan form the interfaces at which cell-cell interactions occur. Consistent with their subcellular location and structural diversity, specific oligosaccharides function as cell-surface tags that allow cells to appropriately interact with each other and with their local environment. In fact, cell surface carbohydrates are among the most discriminating markers for cellular differentiation and pathogenesis. We utilize genetic, molecular, and chemical techniques in vertebrate (mouse) and insect (Drosophila) model systems to study two aspects of carbohydrate expression. First, we investigate the influence of cell surface carbohydrates on development of the nervous system. We identified and characterized a novel carbohydrate binding protein (Gliolectin) that mediates the fidelity of axon pathfinding early in neural development. Second, we study mechanisms that control tissue- and stage-specific oligosaccharide expression. We discovered that a member of the Toll-like receptor family (Tollo) influences tissue-specific glycosylation through cell-cell communication. Our results have implications for facilitating regeneration of axon pathways in the nervous system, for understanding innate immunity and tissue surveillance, and for controlling the cellular changes that precede tumor metastasis.

James Prestegard

jennbryant on July 12, 2021

Short Biography:
Dr. Prestegard received his B.S. in chemistry in 1966 from the University of Minnesota and his Ph.D. in chemistry from the California Institute of Technology in 1971. Prior to joining the CCRC in January 1998, Dr. Prestegard spent 27 years in the Chemistry Department at Yale University where he held positions of assistant professor, associate professor, and professor. In addition to his normal professorial duties, he now directs the regional NMR facilities at the University of Georgia. Dr. Prestegard serves on the editorial boards of several journals, including the Journal of Magnetic Resonance and the Journal of Biomolecular NMR, and is a frequent member of advisory and review panels.

Research Interests:
Dr. Prestegard’s group is applying nuclear magnetic resonance (NMR) spectroscopy to the study of the structure and function of biologically important macromolecular assemblies involving carbohydrates, proteins, and membranes. Research in the Prestegard laboratory focuses on NMR methods development, membrane proteins, cell-surface carbohydrates, protein structure, and protein-protein interactions.

Proteins are large molecules that are targets (receptors) of natural ligands (smaller molecules that bind specifically to the active site of a protein) as well as pharmaceuticals. An essential part of developing any new drug is to determine how that drug will bind to its target protein(s) and to characterize the structures and conformations of the interacting molecules, a particularly difficult task when flexible structures such as carbohydrates are involved. Nuclear magnetic resonance (NMR) spectroscopy is rapidly becoming a major contributor of structural information on how natural ligands and derived drug candidates bind to protein targets. However, progress has been impeded by reliance on short-range interactions (known as NOEs) that are limited in their ability to characterize the relative placement of remote parts of macromolecules or to characterize the average conformation of flexible ligands. These limitations are particularly severe in recognition of carbohydrate-containing ligands because they are inherently flexible and because the proteins that recognize them often function as multimers of loosely connected domains.

The Prestegard group has recently made some important advances in developing non-NOE-based structure determination methods. These methods rely on a more direct NMR measurement that can be made in “ordered” media, in the presence of high magnetic fields. Using these new methods the Prestegard group has succeeded in characterizing the relative orientation of two domains in a carbohydrate-binding protein and in collecting structural data on a flexible trisaccharide (a molecule composed of three sugars) without the use of NOEs. The experiments provide data in a fraction of the time required by the traditional NOE-based approach and can provide a unique structural perspective on which to base the design of new drugs.

NMR methods development. Methods development is closely related to the demands of the applications. For example, some exciting diffusion-edited amide exchange experiments have been developed for the investigation of the energetics and kinetics of protons involved in hydrogen bonds. Hydrogen bonding is important in stabilizing protein structural elements and in protein-carbohydrate recognition, both subjects being studied in the Prestegard group. Neural network-based automated assignment programs for multi-dimensional NMR spectra have been developed, as have statistics-based spectral analysis programs. These programs are essential in achieving less tedious and more precise NMR-based structural analysis.

An ongoing objective of the Prestegard group is to extract new types of information from NMR and related experiments. Current projects involve the use of residual dipolar couplings that occur in molecules oriented by very high magnetic fields and cross-correlation effects that involve chemical shift anisotropies that also become large in high fields. Both topics rely on the design of new experiments and in-depth theoretical analysis of experimental results.

Membrane proteins. The structural analysis of membrane proteins is one of the major challenges in biophysical chemistry today. It is a major challenge because these proteins prefer an environment that is neither crystal nor solution. Unfortunately, crystal and solution phases are the only two phases for which structure determination methods are well established. The Prestegard lab has undertaken the development of NMR-based structure determination methods that are applicable in a medium that mimics the partial, liquid crytalline order of natural membranes. These methods are currently being applied to peptides that present typical membrane protein structural motifs, such as trans bilayer helices and surface-associated amphipathic helices.

Cell-surface carbohydrates. Carbohydrates covalently linked to proteins (glycoproteins) and to lipids (glycolipids) are also present on the surfaces of membranes. In fact, they are the primary mediators in processes that involve interaction of a cell with its external environment. This external environment includes important processes such as cell-cell interactions, hormone stimulation, and invasion by pathogens. Structural characterization of the carbohydrate moieties in their nature environment is essential to understanding and controlling the processes in which they are involved. Many of the NMR methods being developed to characterize membrane proteins are equally applicable to cell-surface carbohydrates. In addition, methods that are more focused on the details of protein-carbohydrate recognition interactions are important. A number of lectins from plant and animal sources are being studied as models for these recognition processes and as a testing ground for methods that can characterize them.

Protein structure and protein-protein interactions. Knowledge of protein structure is essential to understanding a very large number of biochemical processes. However, proteins seldom act alone. They interact with substrates, receptors, and one another to fine tune their activities and specificities. NMR spectroscopy offers the opportunity not only to determine protein structure (in solution, for the cases of interest to the Prestegard group) but to focus on particular regions involved in critical contacts. Isotope-edited NMR experiments are a key component enabling analyses of these special regions. The Prestegard group has implemented a full array of these experiments and is applying them to interesting protein systems. One study involves components of chaperonin systems important to protein folding. Another involves components of multi-enzyme systems important in the synthesis and modification of long chain fatty acids.

Dr. Prestegard’s research is supported by the National Science Foundation, the National Institutes of Health, and the Georgia Research Alliance.

Michael Pierce

jennbryant on July 12, 2021

Short Biography:
Dr. Pierce received his Ph.D. in biology in 1980 from the Johns Hopkins University. Prior to joining the CCRC in April 1991, Dr. Pierce was assistant then associate professor in the Department of Cell Biology and Anatomy at the University of Miami School of Medicine and Staff Investigator of the Papanicolau Comprehensive Cancer Center. In 1988 he was the recipient of a five-year Faculty Research Award from the American Cancer Society. He now serves on the editorial boards of the Journal of Biological Chemistry and Glycobiology. He now serves as Co-Chair of the Alliance for Glycobiologists for Cancer Detection, the Cancer Biology Chair of the Consortium for Functional Glycomics, and 2015 President of the Society for Glycobiology. He is P.I. of the NIGMS National Center for Biomedical Glycomics and Co-P.I. of the NIH Glycoscience Predoctoral Training Program (GTP). His funding comes from NIGMS and NCI.

Research Interests:
Glycan structures change during oncogenesis; these changes are often hallmarks of cancer progression. Our lab investigates:
What are the precise glycan structural changes that occur?
How these changes are regulated at the molecular level?
What are the functional consequences of these changes?
Can these changes be exploited to develop potential diagnostics or therapeutics?
We isolated a cDNA encoding a glycosyltransferase whose activity and product is increased in many cancers, particularly epithelial-derived and showed that its transcript was upregulated via the ras-raf-ets oncogenic signaling pathway.
Our main focus now is on a unique N-glycan whose expression is only on a few proteins in the human genome (protein-site-specific) and appears to be an excellent marker for pancreatic carcinoma.
Discovery of a novel family of innate immune lectins

The X-lectin family is found in deuterostomes from the sea cucumber to man
Over 240 sequences from lectins in this family are now in the database
We isolated the Xenopus laevis cortical granule lectin and with Kelley Moremen showed that it had two human homologs
These human homologs, the intelectins, are constitutively expressed in various endothelial cells, Paneth cells, and are induced in respiratory and intestinal epithelia by IL-13, an innate immune cytokine produced by immune cells
Recent results show intelectin-1 binds and kills specific pathogenic bacteria
We are defining the specificities of the binding sites on various intelectins and working to discover their structures and functions
Here is a recent seminar that I presented as part of the Goldstein Lectureship, University of Michigan Department of Biochemistry and Molecular Biology.

Kelley Moremen

jennbryant on July 12, 2021

Short Biography:

Dr. Moremen received his B.S. in Biology and Chemistry (1978) from Dickinson College and his Ph.D. in Molecular Biology (1984) from Vanderbilt University. Prior to joining the faculty at the CCRC in 1991, he spent five years as a Postdoctoral Fellow at Massachusetts Institute of Technology. Dr. Moremen has served as chair of the Glycobiology Gordon Research Conference, President, Board of Directors, and Secretary of the Society for Glycobiology. He directed efforts on an NIH funded multi-investigator ‘Resource for Integrated Glycotechnology’, served as a senior investigator on the NIH-funded ‘National Center for Biomedical Glycomics’, and is a lead Principal Investigator or Senior Investigator on eight additional grants from the NIH and Department of Energy. In 2018 he launched a biotech startup, Glyco Expression Technologies, Inc., as a part of the UGA Innovation Gateway. He has served on editorial boards of Journal of Biological Chemistry, Glycobiology, and Glycoconjugate Journal, numerous NIH grant review panels, and Scientific Advisory Boards of four biotech companies. In 2014 Dr. Moremen was appointed the Distinguished Research Professorship in Biochemistry and Molecular Biology at the University of Georgia and in 202 was awarded the Karl Meyer Lectureship from the Society for Glycobiology. Dr. Moremen has 10 patents and over 180 publications.

Research Interests:

Research in the Moremen lab focuses on the biochemistry, structure, and regulation of enzymes involved in the biosynthesis, recognition, and catabolism of mammalian glycoproteins. Carbohydrate structures on glycoproteins contribute to many biological recognition events during development, oncogenic transformation, and cell adhesion. Large numbers of intracellular and extracellular proteins contain covalently bound glycans and alterations in the synthesis and degradation of these structures can occur in human genetic diseases and cancer. Many questions remain regarding the regulation of glycosylation pathways, the structures and functions of the processing enzymes, and the specificity and regulation of protein-carbohydrate interactions during development. Research in the Moremen lab is focused on developing novel strategies to address contemporary problems in the regulation, roles, mechanism, and machinery of mammalian protein glycosylation with efforts in four main areas:

1) Structures, specificities and mechanisms of mammalian glycosylation enzymes: Studies on the mammalian glycosylation enzymes in the Moremen lab have expanded in recent years with the development of a unified design and expression platform (Repository of Glycan-related Expression Constructs) for recombinant production of all mammalian glycosyltransferases, glycosidases, and sulfotransferases (target gene list of >400 coding regions) in bacteria, baculovirus, and mammalian cells. This multi-investigator effort, initiated and coordinated within the Moremen lab, is focused on production of these recombinant enzymes and has led to new enzyme structures and insights into the structural basis for enzymatic glycan synthesis. This project has led to numerous additional applications in chemoenzymatic synthesis, biochemical and structural studies, and development of technologies for enzymatic modification of glycoproteins and glycolipids in cellular environments to monitor molecule redistribution in the course of disease. The goals of these studies are to provide a biochemical and structural understanding of glycan biosynthesis and catabolism as well as providing enzymatic catalysts for chemoenzymatic synthesis. This project has been funded by an NIH P01 grant (P01GM107012, Mammalian Glycosyltransferases for Use in Chemistry and Biology) and presently by a multi-investigator NIH R01 grant (R01GM130915, Origin of N-Glycan Site-Specific Heterogeneity). For further information please see: glycoenzymes.ccrc.uga.edu.

2) Protein-carbohydrate interactions: Cell-surface and extracellular glycoproteins and glycolipids play unique and critical roles in mammalian physiology. One of the major glycan classes at the cell surface and within the extracellular matrix are the proteoglycans (PGs) that play diverse roles as co-receptors for cell surface signaling, scaffolds for cell-matrix interactions, ligands that create morphogen or chemokine gradients in development and inflammation, and numerous other contributions to signaling and cell surface structure. Little is known about the details of PG interactions with binding partners or their mechanisms of biological function. The Moremen lab directs a multi-investigator project with goals to develop a novel, integrated technologies that will address the challenges of PG structures, interactions, and biological functions by leveraging advances in analytical, synthetic, structural, biochemical and biological tools. This project has been funded by an NIH P41 grant (P41GM103390, Resource for Integrated Glycotechnology). For further information please see: glycotech.uga.edu.

3) Regulation of glycosylation machinery in mammalian systems: The Moremen lab is also involved in a collaborative project focused on determining the structures and regulation of glycans associated with glycoproteins and glycolipids in animal systems. The overall aims of the program are to examine the changes glycan structures during development with a particular focus on embryonic stem cell differentiation. The Moremen lab has developed platforms for analysis of glyco-gene transcript abundance using a custom real-time RT-PCR strategy as well as next-generation RNA-Seq methods. Integration of the transcript abundance data with the glycan structure analysis developed by other research groups in the CCRC will be accomplished through the bioinformatics group associated with the research program. This project has been funded by an NIH P41 grant (P41GM103490, National Center for Biomedical Glycomics). For further information please see: glycomics.uga.edu

4) Structure and biochemistry of glycan trimming enzymes involved in glycoprotein biosynthesis and catabolism: The fourth area of focus in the Moremen lab is on the enzymes involved in glycan trimming in the secretory pathway that are essential for N-glycan maturation as well as playing a role in the catabolism of misfolded nascent glycoproteins in the endoplasmic reticulum (ER-associated degradation).

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