Fibrils Colocalize Caspase-3 with Procaspase-3 to Foster Maturation

From the Departments of Pharmaceutical Chemistry and.
Journal of Biological Chemistry (Impact Factor: 4.57). 08/2012; 287(40):33781-95. DOI: 10.1074/jbc.M112.386128
Source: PubMed


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 >107-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.

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Available from: Nicholas Agard, Nov 25, 2015
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