>> Protein Ubiquitination
Protein ubiquitination represents a widespread form of post-translational modification, which rivals protein phosphorylation and regulates diverse cellular processes and biological functions. While polyubiquitination of proteins often signals for proteasome-mediated degradation, some forms of ubiquitin-protein conjugates regulate the functions of the target through non-proteolytic mechanisms. We are generally interested in how multi-subunit cullin-RING ubiquitin ligase complexes read and interpret diverse upstream signals to promote ubiquitination of specific protein substrates, and how deubiquitinase complexes assemble and catalyze the reverse reaction to remove the ubiquitin conjugates. Our ongoing research also starts to address how monoubiquitin and polyubiquitin directly control the functions of the target it modifies. (RIGHT: An SCF ubiquitin ligase complex)
>> Plant Biology
Our research were led to the green kingdom of life by ubiquitin ligases, which function as the receptors of several plant hormones. We made our first breakthrough by determining the perception mechanism of the plant hormone auxin, which regulates many aspects of plant physiology. The receptor of auxin had been missing for many decades until it was pinpointed to a plant ubiquitin ligase, TIR1. Our structural studies revealed that auxin surprisingly acts as a "molecular glue" and promotes the interactions between TIR1 and its substrate proteins (transcription repressors) by filling up a gap at the protein-protein interface. We have since become interested in several understudied topics in plant biology, including hormone signaling, nutrient uptake, and stress responses. (Cover story in NATURE)
>> Drug Discovery
Human ubiquitin ligases are numbered in hundreds and present us a completely novel platform for drug discovery. From our studies of auxin perception, we established, for the first time, the concept of "molecular glue", which explains the mechanism of action (MOA) of the master plant hormone. This MOA concept has recently been extended to immunomodulatory drugs (IMiDs), thalidomide and its analogues, a class of medication clinically used for the treatment of cancers and autoimmune diseases. We are interested in applying the concept of molecular glue in discovering novel compounds that can reprogram human ubiquitin ligases for ubiquitinating and degrading disease-related protein substrates. If successful, it will open up entirely new avenues for developing targeted therapeutics.
Mechanism of action of a molecular glue (MG) compound that enables substrate binding to a ubiquitin ligase.
>> Transcription Regulation
Transcription is a complex cellular function that is controlled by many upstream signals and protein machineries. The dynamic epigenetic landscape adds another level of control to gene expression. We are interested in how protein modifications, particularly ubiquitination of histones and transcription factors, are involved in transcription regulation and epigenetic changes. Besides ubiquitin-dependent proteolysis, we begin to appreciate a more active role played by ubiquitin conjugates in directly modulating the functions of the targets. Remarkably, cross-talks among different forms of protein post-translational modifications create even more sophisticated connections among protein networks. We are interested in unraveling the underlying mechanisms by analyzing protein complexes involved in these processes. (LEFT: The DUB module of SAGA)
>> Circadian Clock
Circadian rhythm is a temporal program that synchronizes the cellular time of all living organisms to the earth’s 24-hour solar day. In humans, a master circadian clock is located within the suprachiasmatic nucleus in the brain with peripheral clocks also operating in each cell of the body. In the past two decades, genetic studies have helped identify major circadian clock genes such as PERIOD, CRYPTOCHROME, CLOCK, and BMALs. Yet the precise molecular mechanism by which these gene products sustain and regulate biological clocks remains unclear. Protein ubiquitination again led us into the fascinating world of circadian oscillators. We are interested in using structural biology and biochemistry approaches to understand the inner workings of our biological clock. (RIGHT: PER2 bound to CRY2 with an FAD-binding pocket)
>> Ion Channels
Electrical signaling controls many body functions and underlies all human cognitive activities. Electrical signals are transmitted via action potentials, which are initiated and propagated by voltage-gated ion channels. In a long-standing collaboration with Dr. William Catterall's lab in our department, we have launched a series of in-depth mechanistic studies of voltage-gated sodium channels and voltage-gated calcium channels, which are aimed at uncovering the structural basis of ion selectivity and conductance, voltage sensing, channel activation and inactivation, as well as channel blocking by classic and novel therapeutic drugs. (LEFT: NavAb, a bacterial voltage-gated sodium channel)