6BFO
Caspase-3 Mutant- T245D
6BFO の概要
エントリーDOI | 10.2210/pdb6bfo/pdb |
関連するBIRD辞書のPRD_ID | PRD_000238 |
分子名称 | Caspase-3, AC-ASP-GLU-VAL-ASP-CMK, SODIUM ION, ... (6 entities in total) |
機能のキーワード | allosteric regulation; apoptosis; biophysics; caspase; computational biology; x-ray crystallography; fluorescence; molecular dynamics; protein evolution, apoptosis, apoptosis-inhibitor complex, apoptosis/inhibitor |
由来する生物種 | Homo sapiens (Human) 詳細 |
細胞内の位置 | Cytoplasm: P42574 P42574 |
タンパク質・核酸の鎖数 | 3 |
化学式量合計 | 32693.95 |
構造登録者 | Thomas, M.E.,Grinshpon, R.,Swartz, P.D.,Clark, A.C. (登録日: 2017-10-26, 公開日: 2018-02-21, 最終更新日: 2024-11-20) |
主引用文献 | 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 Cited by 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: 29414778DOI: 10.1074/jbc.RA117.000728 主引用文献が同じPDBエントリー |
実験手法 | X-RAY DIFFRACTION (1.54 Å) |
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