Chemoproteomics Identifies State-Dependent and Proteoform-Selective Caspase-2 Inhibitors.

ABSTRACT: Caspases are a highly conserved family of cysteine-aspartyl proteases known for their essential roles in regulating apoptosis, inflammation, cell differentiation, and proliferation. Complementary to genetic approaches, small-molecule probes have emerged as useful tools for modulating caspase activity. However, due to the high sequence and structure homology of all 12 human caspases, achieving selectivity remains a central challenge for caspase-directed small-molecule inhibitor development efforts. Here, using mass spectrometry-based chemoproteomics, we first identify a highly reactive noncatalytic cysteine that is unique to caspase-2. By combining both gel-based activity-based protein profiling (ABPP) and a tobacco etch virus (TEV) protease activation assay, we then identify covalen

SUBMITTER: Castellon JO 

PROVIDER: S-EPMC11832190 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature