The high temperature requirement A (HTRA) family of serine proteases mediates protein quality control. These proteins process misfolded proteins in several diseases including Alzheimer's disease (AD) and Parkinson's disease (PD). While their structures and activation mechanisms have been studied, the precise details of the regulation of their activity under physiological conditions have not been completely elucidated, partly due to the lack of suitable chemical probes. In the present study, we developed novel activity-based probes (ABPs) targeting the HTRAs and demonstrated their utility in the monitoring and quantification of changes in enzyme activity in live cells. Using our probes, we found the activity of HTRA1 to be highly elevated in an AD-like cell-based model. We also observed the active HTRA2 in live cells by using a mitochondrion-targeted probe. We believe that our probes can serve as a useful tool to study the role of human HTRAs in neurodegenerative diseases.
Bibliographical noteFunding Information:
This work was financially supported by the National Research Foundation of Korea (NRF-2018R1D1A1B07042846 to J.L., NRF-2018R1A2B6007535 to J.S., and NRF-2018M3A9H4079286 to J.-S.L.) and by the GIST Research Institute (GRI) grant to J.S. in 2020.
Copyright © 2020 American Chemical Society.
ASJC Scopus subject areas
- Molecular Medicine