#separase

Cell Division

Which enzyme is responsible for breaking down cohesin to allow sister chromatid separation?

Sister chromatid cohesion mediated by cohesin ring complex with SMC1 and SMC3 coiled-coil proteins forming V-shaped dimer bridged by kleisin Rad21 that closes tripartite ring embracing both sister DNAs from replication until anaphase. Opening requires proteolytic cleavage rather than dissociation. Separase, large 230 kDa cysteine endopeptidase belonging to CD clan with catalytic histidine-cysteine dyad analogous to caspases, serves as cleaving enzyme. Before anaphase, separase kept inactive through two layers: binding of securin pseudosubstrate occupying active site, and cyclin B-CDK1 mediated

Ref: Uhlmann et al., Nature 2000, Mechanism of Separase. Nasmyth, Science 2002, Cohesin Cleavage.

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Cell Cycle Regulation

What is the function of Securin?

Preservation of sister chromatid cohesion until all chromosomes correctly bioriented relies on anaphase inhibitor securin, known as Pds1 in yeast and PTTG1 pituitary tumor transforming gene in mammals. Synthesized during S and G2, securin binds stoichiometric quantities of separase protease through insertion of reactive loop into separase active site, acting as pseudosubstrate and competitive inhibitor. Beyond inhibition, securin serves as chaperone promoting proper folding of separase, its accumulation in nucleus and stability. As long as securin remains associated, separase cannot cleave coh

Ref: Zou et al., Securin as Separase Inhibitor and Chaperone, Cell 1999; Uhlmann et al., Mechanism of Securin-Separase Regulation, Nature 2000.

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Cell Cycle Regulation

The metaphase-to-anaphase transition is triggered by:

The metaphase to anaphase transition is irreversible decision point governed by ubiquitin dependent proteolysis. When every chromosome achieves amphitelic kinetochore-microtubule attachment generating inter-kinetochore tension, spindle assembly checkpoint signaling through MCC production ceases. Dynein-mediated stripping of Mad1-Mad2 from kinetochores and p31comet-TRIP13 catalyzed MCC disassembly liberate coactivator Cdc20, enabling APC/C-Cdc20 ligase activation. Active APC/C polyubiquitinates securin via destruction box motif and cyclin B via D-box for rapid degradation by 26S proteasome. Sec

Ref: Peters, Anaphase Promoting Complex Orchestrating Metaphase-Anaphase Transition, Nat Rev Mol Cell Biol 2006; Alberts et al., Chapter 18, Anaphase.

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Cell Cycle Regulation

Separase is activated when:

Separase activation integrates checkpoint satisfaction with physical separation of chromatids. Newly synthesized separase folds with assistance of securin chaperone, which inserts its own reactive site loop into catalytic pocket, blocking proteolysis and ensuring proper localization to nucleus. Parallel inhibition involves CDK1-Cyclin B1 binding phosphorylating separase at Ser1126 creating docking site for cyclin B. At metaphase, with all kinetochores amphitelically attached, spindle assembly checkpoint silencing allows APC/C-Cdc20 E3 ligase to become active. APC/C-Cdc20 recognizes KEN-box and

Ref: Peters, Control of Securin Degradation by APC/C-Cdc20, Nat Rev Mol Cell Biol; Hornig et al., Securin-Separase Complex Structure.

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