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Professor of Photon Science and of Structural Biology
Current Research and Scholarly InterestsUbiquitin signaling: structure, function, and therapeutics
Ubiquitin is a small protein modifier that is ubiquitously produced in the cells and takes part in the regulation of a wide range of cellular activities such as gene transcription and protein turnover. The key to the diversity of the ubiquitin roles in cells is that it is capable of interacting with other cellular proteins either as a single molecule or as different types of chains. Ubiquitin chains are produced through polymerization of ubiquitin molecules via any of their seven internal lysine residues or the N-terminal methionine residue. Covalent interaction of ubiquitin with other proteins is known as ubiquitination which is carried out through an enzymatic cascade composed of the ubiquitin-activating (E1), ubiquitin-conjugating (E2), and ubiquitin ligase (E3) enzymes. The ubiquitin signals are decoded by the ubiquitin-binding domains (UBDs). These domains often specifically recognize and non-covalently bind to the different ubiquitin species, resulting in distinct signaling outcomes.
We apply a combination of the structural (including protein crystallography, small angle x-ray scattering, cryo-electron microscopy (Cryo-EM) etc.), biocomputational and biochemical techniques to study the ubiquitylation and deubiquitination processes, and recognition of the ubiquitin chains by the proteins harboring ubiquitin-binding domains. Current research interests including SARS-COV2 proteases and their interactions with polyubiquitin chains and ubiquitin pathways in host cell responses, with an ultimate goal of providing strategies for effective therapeutics with reduced levels of side effects.
Protein self-assembly processes and applications.
The Surface layers (S-layers) are crystalline protein coats surrounding microbial cells. S-layer proteins (SLPs) regulate their extracellular, self-assembly by crystallizing when exposed to an environmental trigger. We have demonstrated that the Caulobacter crescentus SLP readily crystallizes into sheets both in vivo and in vitro via a calcium-triggered multistep assembly pathway. Observing crystallization using a time course of Cryo-EM imaging has revealed a crystalline intermediate wherein N-terminal nucleation domains exhibit motional dynamics with respect to rigid lattice-forming crystallization domains. Rate enhancement of protein crystallization by a discrete nucleation domain may enable engineering of kinetically controllable self-assembling 2D macromolecular nanomaterials. In particular, this is inspiring designing robust novel platform for nano-scale protein scaffolds for structure-based drug design and nano-bioreactor design for the carbon-cycling enzyme pathway enzymes. Current research focuses on development of nano-scaffolds for high throughput in vitro assays and structure determination of small and flexible proteins and their interaction partners using Cryo-EM, and applying them to cancer and anti-viral therapeutics.
Multiscale imaging and technology developments.
Multimodal, multiscale imaging modalities will be developed and integrated to understand how molecular level events of key enzymes and protein network are connected to cellular and multi-cellular functions through intra-cellular organization and interactions of the key machineries in the cell. Larger scale organization of these proteins will be studied by solution X-ray scattering and Cryo-EM. Their spatio-temporal arrangements in the cell organelles, membranes, and cytosol will be further studied by X-ray fluorescence imaging and correlated with cryoEM and super-resolution optical microscopy. We apply these multiscale integrative imaging approaches to biomedical, and environmental and bioenergy research questions with Stanford, DOE national labs, and other domestic and international collaborators.
Taia T. Wang, MD, PhD, MSCI
Assistant Professor of Medicine (Infectious Diseases) and of Microbiology and Immunology
Current Research and Scholarly InterestsLaboratory of Mechanisms in Human Immunity and Disease Pathogenesis
Antibodies are a critical component of host defense. While the importance of humoral immunity has been recognized for decades, substantial gaps in knowledge remain around how antibodies function, and how their function is regulated, in vivo. Our laboratory performs studies designed to fill in these gaps, with the goal of enabling new vaccine and therapeutic strategies to prevent human disease. My interest in this area culminated from training in medicine, RNA virus biology (PhD), and molecular antibody biology (postdoctoral training). The intersection of these topics, viral immunity and disease pathogenesis, is the focus of our work. The essential question driving our research is why a small subset of people develop severe or fatal disease during viral infection while most infections result in a subclinical or mild outcome, even in at-risk populations. Our hypothesis is that the antibody signaling pathways that are engaged during viral infection through Fc gamma receptors (FcγRs) are a key driver of these distinct outcomes. We are focused on several major unknowns to address this hypothesis: How are antibody effector functions regulated in vivo and does this change in disease? How do distinct signaling pathways engaged by IgG immune complex-FcγR interactions impact host cell genetic regulation and the ultimate inflammatory/immune response? What are the tissue-specific functions that antibodies engage? How does the heterogeneity in post-translational modifications (PTMs) of human antibodies contribute to heterogeneity in viral immunity?
Current clinical studies:
An Open Label Study of IgG Fc Glycan Composition in Human Immunity
Principal Investigator: Taia T. Wang, MD, PhD
Robert Eckles Swain Professor of Chemistry and Professor, by courtesy, of Chemical Engineering
BioRobert Eckles Swain Professor in Chemistry Robert Waymouth investigates new catalytic strategies to create useful new molecules, including bioactive polymers, synthetic fuels, and sustainable plastics. In one such breakthrough, Professor Waymouth and Professor Wender developed a new class of gene delivery agents.
Born in 1960 in Warner Robins, Georgia, Robert Waymouth studied chemistry and mathematics at Washington and Lee University in Lexington, Virginia (B.S. and B.A., respectively, both summa cum laude, 1982). He developed an interest in synthetic and mechanistic organometallic chemistry during his doctoral studies in chemistry at the California Institute of Technology under Professor R.H. Grubbs (Ph.D., 1987). His postdoctoral research with Professor Piero Pino at the Institut fur Polymere, ETH Zurich, Switzerland, focused on catalytic hydrogenation with chiral metallocene catalysts. He joined the Stanford University faculty as assistant professor in 1988, becoming full professor in 1997 and in 2000 the Robert Eckles Swain Professor of Chemistry.
Today, the Waymouth Group applies mechanistic principles to develop new concepts in catalysis, with particular focus on the development of organometallic and organic catalysts for the synthesis of complex macromolecular architectures. In organometallic catalysis, the group devised a highly selective alcohol oxidation catalyst that selectively oxidizes unprotected polyols and carbohydrates to alpha-hyroxyketones. In collaboration with Dr. James Hedrick of IBM, we have developed a platform of highly active organic catalysts and continuous flow reactors that provide access to polymer architectures that are difficult to access by conventional approaches.
The Waymouth group has devised selective organocatalytic strategies for the synthesis of functional degradable polymers and oligomers that function as "molecular transporters" to deliver genes, drugs and probes into cells and live animals. These advances led to the joint discovery with the Wender group of a general, safe, and remarkably effective concept for RNA delivery based on a new class of synthetic cationic materials, Charge-Altering Releasable Transporters (CARTs). This technology has been shown to be effective for mRNA based cancer vaccines.
William M. Hume Professor in the School of Medicine, Professor of Structural Biology, of Molecular and Cellular Physiology and of Photon Science
Current Research and Scholarly InterestsOur laboratory studies molecular interactions that underlie the establishment and maintenance of cell and tissue structure. Our principal areas of interest are the architecture and dynamics of intercellular adhesion junctions, signaling pathways that govern cell fate determination, and determinants of cell polarity. Our overall approach is to reconstitute macromolecular assemblies with purified components in order to analyze them using biochemical, biophysical and structural methods.
Francis W. Bergstrom Professor and Professor, by courtesy, of Chemical and Systems Biology
Current Research and Scholarly InterestsMolecular imaging, therapeutics, drug delivery, drug mode of action, synthesis
Albert Y. Wu, MD, PhD, FACS
Assistant Professor of Ophthalmology
Current Research and Scholarly InterestsMy translational research focuses on using autologous stem cells to recreate a patient’s ocular tissues for potential transplantation. We are generating tissue from induced pluripotent stem cells to treat limbal stem cell deficiency in patients who are bilaterally blind. By applying my background in molecular and cellular biology, stem cell biology, oculoplastic surgery, I hope to make regenerative medicine a reality for those suffering from orbital and ocular disease.
Joseph C. Wu, MD, PhD
Director, Stanford Cardiovascular Institute, Simon H. Stertzer, MD, Professor and Professor of Radiology
Current Research and Scholarly InterestsDrug discovery, drug screening, and disease modeling using iPSC.