Transit of Procaspase-9 towards its activation. New mechanistic insights from molecular dynamics simulations.

Caspases are cysteine proteases that perform a wide variety of roles in lethal intracellular signaling and cell-death regulation. Caspase-9, the primary initiator caspase of the intrinsic apoptotic pathway, is produced as a scarcely active zymogen (Procaspase-9). Here, we describe, for the first time, at the atomistic level, conformational changes which might be correlated to the activation of Procaspase-9. Molecular dynamics simulations performed at two temperatures (310 and 410 K) provide insights about the conformational space and the time-course evolution of the geometrical and structural characteristics of Procaspase-9. At both temperatures studied, the extremal globular domains of the protein approach each other, contracting the disordered region. In both temperatures, the compact conformations hide more than 40 nm² (about 20% of the total solvent-accessible surface area), and their radius of gyration are reduced by about 40% from the original values. At each temperature, the pathway of contraction is different, as well as the compact structures reached. In consequence, the network of stabilizing interactions at the final conformations is dissimilar. Both final conformations were evaluated in their structural compatibility with the activation models described so far. In this work, we describe mechanistically how and why the activation of Procaspase-9 is favored by apoptosome recruitment via the Caspase Activation Recruitment Domain (CARD), as it has been proposed recently by in vitro experiments.

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