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Modifications to a common phosphorylation network provide individualized control in caspases.

ABSTRACT: Caspase-3 activation and function have been well-defined during programmed cell death, but caspase activity, at low levels, is also required for developmental processes such as lymphoid proliferation and erythroid differentiation. Post-translational modification of caspase-3 is one method used by cells to fine-tune activity below the threshold required for apoptosis, but the allosteric mechanism that reduces activity is unknown. Phosphorylation of caspase-3 at a conserved allosteric site by p38-MAPK (mitogen-activated protein kinase) promotes survival in human neutrophils, and the modification of the loop is thought to be a key regulator in many developmental processes. We utilized phylogenetic, structural, and biophysical studies to define the interaction networks that facilitate the allosteric mechanism in caspase-3. We show that, within the modified loop, Ser¹⁵⁰ evolved with the apoptotic caspases, whereas Thr¹⁵² is a more recent evolutionary event in mammalian caspase-3. Substitutions at Ser¹⁵⁰ result in a pH-dependent decrease in dimer stability, and localized changes in the modified loop propagate to the active site of the same protomer through a connecting surface helix. Likewise, a cluster of hydrophobic amino acids connects the conserved loop to the active site of the second protomer. The presence of Thr¹⁵² in the conserved loop introduces a "kill switch" in mammalian caspase-3, whereas the more ancient Ser¹⁵⁰ reduces without abolishing enzyme activity. These data reveal how evolutionary changes in a conserved allosteric site result in a common pathway for lowering activity during development or a more recent cluster-specific switch to abolish activity.

SUBMITTER: Thomas ME

PROVIDER: S-EPMC5900778 | biostudies-literature |

REPOSITORIES: biostudies-literature

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