Novel Chemical Probes for Selective Tagging of Dimethyl Lysine Posttranslational Modifications and Mediated Protein Protein Interactions

With the support of the Chemistry of Life Processes (CLP) Program in the Division of Chemistry, Monika Raj of Emory University is studying how chemical modification of specific amino acids in proteins influences their role in various biological processes and diseases. Modifications to lysine units in proteins are known to turn on or turn off very important functions inside cells, which are responsible for cell growth and communication between cells.

A deep understanding of lysine modifications and their influence on interactions between proteins is crucial to the development of new molecules that disrupt those protein-protein interactions and may someday serve as therapeutics of various diseases. However, identifying influential lysine modifications is a particularly daunting challenge that has yet to be fully met by traditional biochemical strategies.

Dr. Raj aims to develop new approaches that enable selective chemical labeling of modified lysine units and the linking of protein partners. These innovative chemical approaches are anticipated to provide a general strategy to systematically identify lysine modifications and protein-protein interactions caused by lysine modifications.

Furthering impact of the project are efforts that engage underrepresented individuals across a range of ages, educational levels, and socioeconomic and cultural backgrounds, and encourage their active interest and retention in STEM (Science, Technology, Engineering and Mathematics). Those efforts focus on bringing together a diverse group of graduate and undergraduate students to gain interdisciplinary research training in organic chemistry and biochemistry.

Outreach activities with high school students (especially women and individuals from underrepresented groups) will expose them to basic concepts of biochemistry through fun experimentation and aim to equip them with the social support needed to facilitate the pursuit of a STEM major in college.

Chemical strategies successfully target a particular functional group at a single amino acid site in the presence of reactive amino acid side chains on protein surfaces are limited. Even more rare are organic reactions that can proceed under conditions mild enough to label biomolecules without deleterious effects. To address these challenges, this research project will develop chemical probes based on oxidative coupling with nucleophiles and nucleophilic substitutions that enable site-specific incorporation of photoreactive and affinity groups near modified lysines.

This method will be employed for the site-selective labeling of modified lysine with various cargoes and for capturing protein-protein interactions mediated by modified lysine units. Abnormal lysine modification of a protein can trigger its unique interaction with other proteins, thus leading to a variety of different diseases; however, the chemical methods for selective detection of lysine modification and associated protein-protein interactions are still lacking.

This research will provide highly selective chemical probes that can effectively detect modified lysine and capture their protein partners. Thus, the proposed research has a great potential to further our understanding of how these lysine modifications and their aberrations regulate various cellular signaling processes and lead to various diseases.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.