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| Title | Structural basis of human separase regulation by securin and CDK1-cyclin B1. |
|---|---|
| Journal, issue, pages | Nature, Vol. 596, Issue 7870, Page 138-142, Year 2021 |
| Publish date | Jul 21, 2021 |
 Authors | Jun Yu / Pierre Raia / Chloe M Ghent / Tobias Raisch / Yashar Sadian / Simone Cavadini / Pramod M Sabale / David Barford / Stefan Raunser / David O Morgan / Andreas Boland /     |
| PubMed Abstract | In early mitosis, the duplicated chromosomes are held together by the ring-shaped cohesin complex. Separation of chromosomes during anaphase is triggered by separase-a large cysteine endopeptidase ...In early mitosis, the duplicated chromosomes are held together by the ring-shaped cohesin complex. Separation of chromosomes during anaphase is triggered by separase-a large cysteine endopeptidase that cleaves the cohesin subunit SCC1 (also known as RAD21). Separase is activated by degradation of its inhibitors, securin and cyclin B, but the molecular mechanisms of separase regulation are not clear. Here we used cryogenic electron microscopy to determine the structures of human separase in complex with either securin or CDK1-cyclin B1-CKS1. In both complexes, separase is inhibited by pseudosubstrate motifs that block substrate binding at the catalytic site and at nearby docking sites. As in Caenorhabditis elegans and yeast, human securin contains its own pseudosubstrate motifs. By contrast, CDK1-cyclin B1 inhibits separase by deploying pseudosubstrate motifs from intrinsically disordered loops in separase itself. One autoinhibitory loop is oriented by CDK1-cyclin B1 to block the catalytic sites of both separase and CDK1. Another autoinhibitory loop blocks substrate docking in a cleft adjacent to the separase catalytic site. A third separase loop contains a phosphoserine that promotes complex assembly by binding to a conserved phosphate-binding pocket in cyclin B1. Our study reveals the diverse array of mechanisms by which securin and CDK1-cyclin B1 bind and inhibit separase, providing the molecular basis for the robust control of chromosome segregation. |
 External links | Nature / PubMed:34290405 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.9 - 3.6 Å |
| Structure data | EMDB-12368, PDB-7nj0: EMDB-12369, PDB-7nj1: |
| Chemicals |  ChemComp-PO4: |
| Source |
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 Keywords |  HYDROLASE / autoinhibition phosphate-binding pocket pseudosubstrate Scc1 / pseudosubstrate HEAT repeat caspase cell cycle |
