Wells LabUCSF, Depts of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology
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Protease Signaling Pathways

Proteases are essential enzymes for digestion, signaling and remodeling of the inside and outside of the cell. A major challenge for understanding the role of proteases in biology is figuring out what they actually cut. We have recently developed a new approach to tagging and purifying the products of a cleavage reaction so that the specific cut site can be identified by mass spectrometry. We have engineered an enzyme, subtiligase, that is able to ligate small biotinylated peptides onto exposed N-termini, tagging them for enrichment and identification by mass spectrometry. This novel technology has already allowed us to detect many new caspase cleavage events against the complex background of a whole cell extract.

The potential uses of this technology for proteomics research are almost endless. It can be used to study the targets of the more than 500 human proteases, plus the hundreds of important proteases in disease-causing organisms. We are currently focusing on human caspases, by studying cleavage products in cells induced to apoptose or to undergo an innate immune response.