Activity-Based Probes for the High Temperature Requirement A Serine Proteases

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.