Abstract:

My laboratory has made significant advancements in understanding the unconventional roles of uncharacterized and understudied protein kinases and pseudokinases. Over the past ten years, we have uncovered unexpected biochemical functions within this protein family, including AMPylation, polyglutamylation, and mRNA capping via RNAylation. Our approach employs a multifaceted strategy, beginning with the bioinformatic identification of atypical family members. We then use biochemistry, structural biology, and mass spectrometry to reveal unique functions and previously undiscovered enzymatic activities that could not have been predicted a priori.

While traditional sequence-based bioinformatics approaches have been highly effective in identifying new kinase families, integrating AI-driven tools like AlphaFold into our experimental pipeline has been a transformative advancement. In this lecture, I will present two recent discoveries from my laboratory that harnessed AI to identify orphan kinases in the ether lipid and isoprenoid salvage pathways.

Bio:

I received my PhD in 2010 from Indiana University with Peter Roach and did postdoctoral work at UC San Diego with Jack Dixon, where I discovered Fam20C as the kinase that phosphorylates secreted proteins, including casein. In 2015, I began my independent position in the Department of Molecular Biology at UTSW and was named an investigator with the Howard Hughes Medical Institute (HHMI) in 2021.

My lab has advanced our understanding of non-canonical functions for protein kinases by discovering diverse and unexpected biochemical activities within this protein superfamily. We discovered that the pseudokinases SelO, SidJ, and nsp12 catalyze AMPylation, polyglutamylation, and mRNA capping via RNAylation, respectively. These findings provide new insights into the cellular response to oxidative stress and the mechanisms of bacterial and viral pathogens. Our work highlights the catalytic versatility of the protein kinase fold and suggests that pseudoenzymes should be analyzed for alternative catalytic activities.