Conformational transitions of caspase-6 in substrate-induced activation process explored by perturbation-response scanning combined with targeted molecular dynamics.

Caspase-6 participates in a series of neurodegenerative pathways, and has aroused widespread attentions as a promising molecular target for the treatment of neurodegeneration. Caspase-6 is a homodimer with 6 central-stranded β-sheets and 5 α-helices in each monomer. Previous crystallographic studies suggested that the 60's, 90's and 130's helices of caspase-6 undergo a distinctive conformational transition upon substrate binding. Although the caspase-6 structures in apo and active states have been determined, the conformational transition process between the two states remains poorly understood. In this work, perturbation-response scanning (PRS) combined with targeted molecular dynamics (TMD) simulations was employed to unravel the atomistic mechanism of the dynamic conformational transitions underlying the substrate-induced activation process of caspase-6. The results showed that the conformational transition of caspase-6 from apo to active states is mainly characterized by structural rearrangements of the substrate-binding site as well as the conformational changes of 60's and 130's extended helices. The H-bond interactions between L1, 130's helix and 90's helix are proved to be key determinant factors for substrate-induced conformational transition. These findings provide valuable insights into the activation mechanism of caspase-6 as well as the molecular design of caspase-6 inhibitors.

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© 2021 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.

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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.