SLAC National Accelerator Laboratory
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Soichi Wakatsuki
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. -
Risa Wechsler
Director, Kavli Institute for Particle Astrophysics and Cosmology (KIPAC), Humanities and Sciences Professor and Professor of Physics and of Particle Physics and Astrophysics
BioRisa Wechsler is the Humanities and Sciences Professor and Professor of Physics in the School of Humanities and Sciences and Professor of Particle Physics & Astrophysics at SLAC National Laboratory. She is the Director of the Kavli Institute of Particle Astrophysics and Cosmology and the Center for Decoding the Universe and an Associate Director at Stanford Data Science. She is a cosmologist whose work investigates some of the most profound questions about our universe — how it formed, what it is made of, how it is structured, and what its future holds.
Her research focuses on understanding the evolution of galaxies, the large-scale structure of the universe, and the nature of dark matter and dark energy. She uses large numerical simulations, theoretical models, and the largest observed maps of the universe to explore these forces that shape the cosmos. Her recent work also investigates the formation and cosmological context of the Milky Way and probes dark matter through small-scale cosmic structure, and explores how data science and AI/ML can drive new understanding. Wechsler has played key leadership roles in major international collaborations including the Dark Energy Survey, Dark Energy Spectroscopic Instrument, and Rubin Observatory's Legacy Survey of Space and time, a decade-long survey that will reveal the dynamic universe in unprecedented detail. She is recently involved in the Via Survey, which will map the Milky Way at high precision to probe dark matter physics in new ways.
Wechsler is an elected member of the National Academy of Sciences and the American Academy of Arts and Sciences and a Fellow of the American Physical Society and the American Association for the Advancement of Science.