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Scientific article
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Cryo-EM structure of a metazoan separase–securin complex at near-atomic resolution

Published inNature structural & molecular biology, vol. 24, no. 4, p. 414-418
Publication date2017-03-06
First online date2017-03-06
Abstract

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 α-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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Affiliation Not a UNIGE publication
Funding
  • UK Research and Innovation - Mechanism of chromosome segregation in mitosis [MC_UP_1201/6]
  • UK Research and Innovation - Visualising proteins in health and disease [MC_UP_A025_1013]
  • Cancer Research UK - [C576/A14109]
  • Long Term EMBO Fellowships - [ALTF 79-2014]
  • Long Term EMBO Fellowships - [ALTF 1229-2013]
  • European Commission - Molecular basis for securin and cyclin ubiquitylation by the anaphase-promoting complex (APC/C) [657725]
Citation (ISO format)
BOLAND, Andreas et al. Cryo-EM structure of a metazoan separase–securin complex at near-atomic resolution. In: Nature structural & molecular biology, 2017, vol. 24, n° 4, p. 414–418. doi: 10.1038/nsmb.3386
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Article (Accepted version)
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ISSN of the journal1545-9985
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