title: Fibrils colocalize caspase-3 with procaspase-3 to foster maturation.
abstract: Most proteases are expressed as inactive precursors, or zymogens, that become activated by limited proteolysis. We previously identified a small molecule, termed 1541, that dramatically promotes the maturation of the zymogen, procaspase-3, to its mature form, caspase-3. Surprisingly, compound 1541 self-assembles into nanofibrils, and localization of procaspase-3 to the fibrils promotes activation. Here, we interrogate the biochemical mechanism of procaspase-3 activation on 1541 fibrils in addition to proteogenic amyloid-β(1-40) fibrils. In contrast to previous reports, we find no evidence that procaspase-3 alone is capable of self-activation, consistent with its fate-determining role in executing apoptosis. In fact, mature caspase-3 is >10(7)-fold more active than procaspase-3, making this proenzyme a remarkably inactive zymogen. However, we also show that fibril-induced colocalization of trace amounts of caspase-3 or other initiator proteases with procaspase-3 dramatically stimulates maturation of the proenzyme in vitro. Thus, similar to known cellular signaling complexes, these synthetic or natural fibrils can serve as platforms to concentrate procaspase-3 for trans-activation by upstream proteases.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Zorn
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Wolan
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Agard
authors.forename: James A
authors.initials: JA
authors.lastname: Wells
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry; D017209:Apoptosis; D053148:Caspase 3 / Q000737:chemistry*; D002384:Catalysis; D019281:Dimerization; D016503:Drug Delivery Systems; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D008956:Models, Chemical; D010447:Peptide Hydrolases / Q000737:chemistry; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D016229:Amyloid beta-Peptides; D004792:Enzyme Precursors; D010447:Peptide Hydrolases; D053148:Caspase 3