Separase is a large (140-250 kD) eukaryotic endopeptidase belonging to the CD clan of cysteine proteases, which also includes caspases and gingipain. It has essential roles in chromosome segregation, by cleaving the kleisin subunit (Scc1/Rad21/Mcd1 for mitosis and Rec8 for meiosis) of the cohesin complex that entraps sister chromatids during cell division. It also has important functions in other cellular events, such as stabilizing the anaphase spindle by cleaving and localizing the kinetochore-associated protein Slk19, and regulating centriole disengagement in mammals by cleaving pericentrin/kendrin. Overexpression of separase is linked to aneuploidy and tumorigenesis, making it a potential target for drug discovery.
The activity of separase is tightly regulated. Securin, a natively unfolded protein in solution, acts as both a chaperone and a potent inhibitor of separase.
The primary structure of separase contains a C-terminal caspase-like catalytic domain (CD) of ~200 residues and an N-terminal a-helical regulatory region, which is poorly conserved. Securin has a KEN-box and a D-box in its N-terminal region which are crucial for ubiquitination by APC/C, while its C-terminal region mediates the binding and inhibition of separase.Major findings from this project
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