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Comparing the folding landscapes of evolutionarily divergent procaspase-3

Liqi Yao, A. Clay Clark
doi: https://doi.org/10.1101/2022.01.12.476064
Liqi Yao
1Department of Biology, University of Texas at Arlington, Arlington, Texas, 76019
2Department of Biochemistry, University of Colorado at Boulder, Boulder, Colorado, 80303
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A. Clay Clark
1Department of Biology, University of Texas at Arlington, Arlington, Texas, 76019
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  • For correspondence: clay.clark@uta.edu
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Abstract

All caspases evolved from a common ancestor and subsequently developed into two general classes, inflammatory or apoptotic caspases. The caspase-hemoglobinase fold has been conserved throughout nearly one billion years of evolution and is utilized for both the monomeric and dimeric subfamilies of apoptotic caspases, called initiator and effector caspases, respectively. We compared the folding and assembly of procaspase-3b from zebrafish to that of human effector procaspases in order to examine the conservation of the folding landscape. Urea-induced equilibrium folding/unfolding of procaspase-3b showed a minimum three-state folding pathway, where the native dimer isomerizes to a partially folded dimeric intermediate, which then unfolds. A partially folded monomeric intermediate observed in the folding landscape of human procaspase-3 is not well-populated in zebrafish procaspase-3b. By comparing effector caspases from different species, we show that the effector procaspase dimer undergoes a pH-dependent conformational change, and that the conformational species in the folding landscape exhibit similar free energies. Together, the data show that the landscape for the caspase-hemoglobinase fold is conserved, yet it provides flexibility for species-specific stabilization or destabilization of folding intermediates resulting in changes in stability. The common pH-dependent conformational change in the native dimer, which yields an enzymatically inactive species, may provide an additional, albeit reversible, mechanism for controlling caspase activity in the cell.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted January 12, 2022.
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Comparing the folding landscapes of evolutionarily divergent procaspase-3
Liqi Yao, A. Clay Clark
bioRxiv 2022.01.12.476064; doi: https://doi.org/10.1101/2022.01.12.476064
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Comparing the folding landscapes of evolutionarily divergent procaspase-3
Liqi Yao, A. Clay Clark
bioRxiv 2022.01.12.476064; doi: https://doi.org/10.1101/2022.01.12.476064

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