Asst Professor

Biochemistry

West Virginia University School of Medicine

Instructor

Cell Biology

Harvard Medical School (Boston, MA)

Post Doctoral Fellow

Cell Biology

Harvard Medical School (Boston, MA)

Alfred L Goldberg

I am interested in studying the detailed molecular mechanisms that are involved in protein degradation by the 26S proteasome, beginning with substrate recognition and ending in protein degradation. I also wish to understand how other novel complexes regulate proteasome function and what biological roles they might play.

During my graduate studies I discovered, developed and characterized several novel inhibitors of the proteasome—the critical ATP-dependent proteolytic complex in eukaryotes—and studied their effects on cell cycle and apoptosis in cancer cell models. As a postdoctoral fellow I have used biochemical, biophysical, and structural techniques to elucidate the mechanism of proteasome function, which is surprisingly poorly understood.

My postdoctoral studies have shown how the regulatory ATPase complex in the eukaryotic 26S proteasome controls the entry of substrates into its degradation chamber. I have discovered a new domain in these proteasomal ATPases that regulates protein degradation by opening a gate that controls substrate entry, much like a “key-in-a-lock” (Smith et al. Mol. Cell 2007). We have also elucidated the structural changes that are induced by binding of the “key” domain that is associated with the gate-opening step (Rabl*, Smith* et. al. Mol. Cell 2008). My further studies clarified the 30-year-old paradox of why the proteasome requires energy from ATP hydrolysis when the cleavage of a peptide bond itself is energetically a downhill process. These studies deconstructed the roles of ATP in the multistep process of protein degradation and uncovered a novel mechanism for the translocation of substrates into the degradative core (Smith et al. Mol. Cell 2005). In addition, my work has established that the evolutionarily conserved 20S proteasome and regulatory ATPase ring from archaea associate to catalyze protein degradation and that the structure of this complex is remarkably similar to the eukaryotic 26S proteasome. These findings established the simpler archaeal proteasome-ATPase complex as an excellent model to investigate the more complex 26S proteasome.

My current lab will focus on understanding the functions of the eukaryotic proteasome at a molecular level. See my lab home page for more information on my current interests. (http://tinyurl.com/3zpuj4m)

2006-2008 Medical Foundation Fellowship