期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 24, 期 4, 页码 414-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.3386
关键词
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资金
- Medical Research Council [MC_UP_1201/6, MC_UP_A025_1013]
- Cancer Research UK [C576/A14109]
- EMBO [ALTF 79-2014, ALTF 1229-2013]
- H2020 Marie-Curie Fellowships [657725, 657990]
- Wellcome Trust
- MRC
- BBSRC
- MRC [MC_UP_A025_1013, MC_UP_1201/6] Funding Source: UKRI
- Cancer Research UK [14109, 24307] Funding Source: researchfish
- Medical Research Council [MC_UP_A025_1013, MC_UP_1201/6] Funding Source: researchfish
- Marie Curie Actions (MSCA) [657990, 657725] Funding Source: Marie Curie Actions (MSCA)
Separase is a caspase-family protease that initiates chromatid segregation by cleaving the kleisin subunits (Scc1 and Rec8) of cohesin, and regulates centrosome duplication and mitotic spindle function through cleavage of kendrin and Slk19. To understand the mechanisms of securin regulation of separase, we used single-particle cryo-electron microscopy (cryo-EM) to determine a near-atomic-resolution structure of the Caenorhabditis elegans separase-securin complex. Separase adopts a triangular-shaped bilobal architecture comprising an N-terminal tetratricopeptide repeat (TPR)-like alpha-solenoid domain docked onto the conserved C-terminal protease domain. Securin engages separase in an extended antiparallel conformation, interacting with both lobes. It inhibits separase by interacting with the catalytic site through a pseudosubstrate mechanism, thus revealing that in the inhibited separase-securin complex, the catalytic site adopts a conformation compatible with substrate binding. Securin is protected from cleavage because an aliphatic side chain at the P1 position represses protease activity by disrupting the organization of catalytic site residues.
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