NSF Award
2414075
With the support of the Chemistry of Life Processes (CLP) program in the Division of Chemistry, Professors Shina Kamerlin of Georgia Institute of Technology, Sean Johnson and Alvan Hengge of Utah State University are studying the evolution of archaeal protein tyrosine phosphatases (PTPs). PTPs are a family of enzymes that play crucial roles in regulating cellular signaling processes. A characteristic feature of these enzymes is a flexible region that plays an important role in controlling catalytic activity. However, it is not well understood how the flexibility of this region is regulated. The proposed experiments will explore how these motions are achieved in archaeal PTPs and evolutionary ancestors. The proposed work will shed light on the role of enzyme dynamics in evolution, and will ultimately impact multiple fields from drug discovery to protein engineering. This pursuit allows graduate students to acquire specialized training in computational biophysics, structural biology, enzyme biochemistry, and NMR spectroscopy. The project includes outreach and mentorship activities to increase the participation of women and other underrepresented students in STEM. Further, the project endeavors to bring science to the general public through participation in festivals, lecture series, and radio broadcasts.<br/><br/>This research project seeks to quantitatively characterize the evolution of loop motion and allostery in archaeal protein tyrosine phosphatases, by using advanced biomolecular simulations, intimately coupled with X-ray crystallography, kinetic characterization, and NMR spectroscopy. This will be achieved through characterization of both several extant PTPs, as well as a range of ancestral archaeal PTPs predicted from ancestral sequence reconstruction. Comparison of these enzymes to human and bacterial PTPs will shed light into the factors governing loop motion in PTPs, and how it has changed over evolutionary time. This provides important fundamental insight into enzyme evolution more broadly, as well as identifying features that can be exploited for protein engineering.<br/><br/>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.
