UCSF

Proteolysis is unique among post translational modifications because it is irreversible. The specific recognition of protein termini is an essential mechanism by which proteolytic enzymes mediate signaling in biology. The identification of terminal recognition elements with complimentary specificity to proteases, often as part of an E3 ubiquitin ligase, has facilitated the elucidation of protease signaling pathways that function in critical cellular processes. The caspase family of protease are well known for their role in directing the fate of the cell by initiating and executing inflammatory and death-related signaling cascades. The biochemical feature that unites this family of enzymes is the ability to hydrolyze a peptide bond following and aspartic acid. We have determined that the TPR family of co-chaperones, including the E3 ubiquitin ligase CHIP, can also bind to a subset of new C-termini generated by caspase activity. These co-chaperones were though to function predominantly, if not exclusively, by interacting with a conserved Glu-Glu-Val-Asp at the C-terminus of cytosolic Hsp70s and 90s. This work has uncovered new functions for both caspases and TPR co-chaperones and has identified a dedicated molecular framework for caspases and protein homeostasis networks to exchange information. These systems play a critical role in balancing cell fate in development and disease making it likely that critical signaling nodes occur at this interface.