6BFK

Caspase-3 Mutant- T245A

Summary for 6BFK

• Entry DOI: 10.2210/pdb6bfk/pdb
• Related PRD ID: PRD_000238
• Descriptor: Caspase-3, AC-ASP-GLU-VAL-ASP-CMK, SODIUM ION, ... (5 entities in total)
• Functional Keywords: allosteric regulation; apoptosis; biophysics; caspase; computational biology; x-ray crystallography; fluorescence; molecular dynamics; protein evolution, apoptosis, apoptosis-inhibitor complex, apoptosis/inhibitor
• Biological source: Homo sapiens (Human); More
• Cellular location: Cytoplasm: P42574 P42574
• Total number of polymer chains: 6
• Total formula weight: 64740.98

Authors

Thomas, M.E.,Grinshpon, R.,Swartz, P.D.,Clark, A.C. (deposition date: 2017-10-26, release date: 2018-02-21, Last modification date: 2024-11-20)

Primary citation

Thomas, M.E.,Grinshpon, R.,Swartz, P.,Clark, A.C.
Modifications to a common phosphorylation network provide individualized control in caspases.
J. Biol. Chem., 293:5447-5461, 2018

PubMed 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, Ser evolved with the apoptotic caspases, whereas Thr is a more recent evolutionary event in mammalian caspase-3. Substitutions at Ser 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 Thr in the conserved loop introduces a "kill switch" in mammalian caspase-3, whereas the more ancient Ser 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.

PubMed: 29414778
DOI: 10.1074/jbc.RA117.000728

Experimental method

X-RAY DIFFRACTION (1.753 Å)