Structural basis of cohesin cleavage by separase

Area of Science:

• Molecular Biology
• Structural Biology
• Cell Biology

Background:

• Accurate chromosome segregation is vital for cell division, requiring timely dissolution of chromosome cohesion.
• Separase is the key enzyme responsible for cleaving cohesin, enabling chromosome segregation.
• Dysregulation of this process leads to aneuploidy, associated with cancer and birth defects.

Purpose of the Study:

• To determine the atomic structures of the separase protease domain.
• To elucidate the mechanisms of cohesin recognition and cleavage by separase.
• To understand the role of cohesin phosphorylation in regulating separase activity.

Main Methods:

• X-ray crystallography was used to obtain structures of the separase protease domain.
• Structures were determined for separase alone and in complex with inhibitory peptides.
• Mutagenesis studies were performed on securin to investigate its interaction with separase.

Main Results:

• Crystal structures of the Chaetomium thermophilum separase protease domain were determined.
• Structures reveal how separase recognizes cohesin and how phosphorylation enhances cleavage.
• Mutations in securin can convert it from an inhibitor to a substrate for separase.

Conclusions:

• The study provides atomic insights into separase-mediated cohesin cleavage.
• Cohesin phosphorylation by Plk1 enhances separase activity.
• Securin's inhibitory mechanism and potential substrate conversion are elucidated.