Soichi Wakatsuki
Soichi Wakatsuki is a Professor of Photon Science at the SLAC National Accelerator Laboratory where he recently initiated the Biociences Division, and Professor of Structural Biology, Stanford School of Medicine. He received his B.S and M.S. degrees in Chemical Engineering from University of Tokyo, and his Ph.D. degree in Chemistry from Stanford University in 1991. After postdoctoral studies on time-resolved x-ray crystallography of enzyme reactions in Oxford (1990 to 1994), he moved to Grenoble, France in 1994 to work at the European Synchrotron Radiation Facility (ESRF) where he led Joint Structural Biology Group to develop high-brilliance x-ray crystallography beamlines and instruments, as well as several structural biology projects on protein transport. In 2000, Soichi moved back to Japan to start a new Structural Biology Research Center at KEK (High Energy Accelerator Research Organization), Tsukuba, Japan, and later served as Director of Photon Factory (national synchrotron radiation facility) from 2006 to 2012. There he further developed x-ray beamlines and a large scale protein crystallization system, led initiatives to start three national projects on structural proteomics. Fascinated by new research opportunities in integrative bioimaging at Stanford and the world’s first hard x-ray free electron laser (XFEL) at SLAC, Soichi returned to Stanford in 2013. Soichi’s research interests include structural biology of post-translational modification and vesicle transport, structural biology of polyubiquitin recognition, synchrotron radiation and XFEL instrumentation, protein crystallography and small angle X-ray scattering, integrative multi-scale bioimaging.
Areas of Interest and Research
Ubiquitin 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.