Research

The Yu lab at GSU is dedicated to developing innovative chemical tools to study signal transduction and medicine in the context of protein-protein interactions (PPIs). PPIs play pivotal roles in regulating a variety of signaling pathways and their dysfunction often leads to disease progression. The lack of enabling chemical tools leads to the unresolved roles of PPIs in numerous diseases. The current method of capturing PPIs such as affinity purification-mass spectrometry relies on the reversible interactions between proteins, which often leads to large variation, false positive signals, and cannot distinguish direct from indirect interactors. UV-mediated cross-linking, although has greatly advanced this field, lacks specificity. We aim to probe PPIs via two strategies: protein engineering and small molecule probe constructions. 
 
1. Probing PPIs via Genetically Encoded Chemical Cross-linking (GECX).

 

This strategy genetically incorporates fluorosulfate-L-tyrosine (FSY), a latent bioreactive unnatural amino acid (Uaa), into a protein of interest. Upon protein-target binding, FSY would be brought into close proximity to a nucleophile on the target proteins, which enables FSY to react with the nucleophile on the target proteins via sulfur fluoride exchange (SuFEx), irreversibly cross-linking the interacting proteins. Subsequent cross-linked peptides identification via mass spectrum would reveal the interacting proteins in high specificity. Initially, we will probe protein post-translational modification (PTM)-mediated PPIs and identify new PPIs as therapeutic targets. This site-specific Uaa incorporation allows us to probe PPIs in a domain-specific manner.