This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).
Intellectual Merit. When new proteins are synthesized, they emerge in an extended, linear conformation and must be folded into their final, three-dimensional shapes before they acquire function. The cellular network responsible for supervising this process includes a large family of molecular chaperones. Chaperones bind to unfolded proteins and direct them towards a folded state; however, these same chaperones can also direct terminally misfolded proteins to the proteasome for degradation. This CAREER proposal will explore how chaperones make this critical decision to fold or degrade proteins. The specific approach is to acutely perturb this system with new chemical probes to understand how specific chaperone components contribute. This discovery process is expected to provide new insights into how chaperones govern protein folding in the complex environment of the cell.
Broader Impact. A key educational goal of this CAREER project is to illuminate the benefits that originate at the interface between chemical methodologies, fundamental biological inquiries and enabling scientific instrumentation. Towards this goal, chaperones will be distributed to groups of young high school and undergraduate scientists-in-training for chemical screening, in collaboration with the University of Michigan's Center for Chemical Genomics. The goals of this effort are two-fold: (a) to broaden the scientific impact of the CAREER project through expanded screening of potential chaperone targets and (b) to mentor and educate young scientists about modern discovery methods, using high-end equipment not typically available in the average teaching laboratory. In this task, the teamwork and excitement required to address important questions in modern chemical biology will be highlighted.
