Dissecting Molecular Mechanisms of Signaling Pathways and their Regulation by Proteolytic System

All kingdoms of life have evolved to sense signals such as light, gravity, temperature, oxygen, metabolites, and hormones.  Once perceived, these signals are transduced into developmental and physiological responses by reprogramming appropriate genes.

In eukaryotes, the ubiquitin (Ub) system has emerged at the center of many signaling mechanisms through their targeting of specific key proteins for ubiquitination and degradation by the 26S proteasome.  The specificity of ubiquitination is conferred by Ub E3 ligase complexes, which serves as the substrate receptor and recruits E2 enzymes that catalyze transfer of Ub to a substrate lysine. Typically, E3s recognize substrates that are modified, often by phosphorylation. In addition to other forms of post-translational modification such as hydroxylation, acetylation and glycosylation, the last decade has witnessed an increasing number of studies identifying small-molecules such as hormones that directly mediate substrate recognition. Despite the significant advances made in understanding the cellular mechanisms that underlie signal-dependent substrate recognition by the Ub system, this field is largely unexplored. This notion is especially significant given the number of uncharacterized E3 ligases, target substrates, and countless signals that are yet to be unveiled.  Our research aims to reveal and dissect how E3 ligases regulate cellular response to a variety of stimuli, and what the roles are of other components of the Ub system, including deubiquitinating enzymes, and Ub-like proteins in plants.

Our research focus expands also beyond the Ub system’s role in signaling pathways.  We aim to decode and provide mechanistic insight into the basis of signal recognition and propagation pathways in cells. We are particularly interested in characterizing signal transduction pathways that are triggered by environmental stimuli such as in photomorphogenesis, gravitropism and mechanoperception.  What are the precise biochemical adaptations, and how do they render a specific biomolecular sensor to be promptly recognized by yet another regulatory protein (e.g., transcription factor)? All these questions remain to be answered for many biological pathways.

Our lab address these fundamental challenges by leveraging structural biology (X-ray crystallography and Cryo-EM) approaches in combination with biochemistry, molecular and cellular biology, proteomics, and metabolomics methods.

 

Applied Research and Biotechnology

How can we learn from cellular machines and utilize them to innovate and improve medical and agriculture technologies? How can we direct molecular mechanisms such as the ubiquitin-system to fight cancer, neurodegenerative disorders, viruses and other pathogens?  In our second line of research, we aim to design and develop tools to address imperative challenges in the fields of human health, agriculture and environment.   To that end, we are focusing on (i) developing a cost-effective technology to accelerate large-scale production of functional proteins from various biological expression systems,  (ii) bioengineering dedicated molecular machines based on structural analyses and accelerated evolution approaches, (iii) screening and designing small-molecules (agonists or antagonists) targeting protein-protein interactions for therapeutic interventions.