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Brian P. Callahan


Assistant Professor, Biological Chemistry

Research Interests

Overview: We investigate the molecular mechanisms of two essential events in the expression of genetic information: protein biogenesis and protein degradation. Research projects can be hypothesis or technology driven, with opportunities to acquire training in chemical kinetics, protein engineering, bioseperations, small molecule synthesis, and various types of spectroscopy.

Protein Biogenesis: Hedgehog and intein-containing proteins contribute to the pathology of major human diseases, including tuberculosis and multiple types of cancer, as well as to serious birth defects. Our research focuses on understanding the autocatalytic protein splicing reactions carried out by these "HINT" proteins. Mechanisms of protein splicing are diverse, but each reaction serves to transform inactive precursors into functional molecules, i.e. biogenesis. Major roadblocks to investigating this crucial process include the near absence of activity assays and the paucity of high-resolution structural data on HINT precursors. We are now addressing these gaps in support of our research objectives, which include:

  1. To identify, or enable other labs to identify, small-molecules that modulate protein splicing activity as translational medicines.
  2. To engineer the splicing activity of HINT domains for applied uses in biochemistry, bioimaging and drug discovery.
  3. To characterize a complete protein splicing reaction at atomic resolution.

Protein Degradation: An additional area of research centers on the design of genetically encoded biosensors for in vitro and in vivo enzymology. We are particularly interested in developing biosensors to detect and monitor the action of proteolytic enzymes, or proteases. Recently we engineered green fluorescent protein (GFP) to function as the first fluorogenic biosensor of protease activity. We are now developing a variegated family of protease biosensors to facilitate assay multiplexing. A related project seeks to exploit our biosensors to define the substrate specificity of novel proteases as well as to “breed” proteases that cleave at user-defined sequences.