Two-step ATP-driven opening of cohesin head

Area of Science:

• Molecular Biology
• Biochemistry
• Structural Biology

Background:

• The cohesin ring complex, comprising Smc1A, Smc3, Rad21, and Stag1/2, is crucial for chromosome segregation, DNA repair, chromatin organization, and gene transcription.
• Ring opening, essential for cohesin function, occurs at the head structure formed by the ATPase domains of Smc1A, Smc3, and Rad21.

Purpose of the Study:

• To elucidate the atomic-scale mechanisms governing cohesin ring opening.
• To investigate the sequential activation of ATPase sites and the role of specific domains and amino acids in the opening process.

Main Methods:

• Free molecular dynamics (MD) simulations.
• Steered molecular dynamics (MD) simulations.
• Quantum mechanics/molecular mechanics (QM/MM) MD simulations.

Main Results:

• Detailed atomic-scale analysis of cohesin ring opening events.
• Identified ATP hydrolysis at the Smc1A site and its influence on the Rad21 carboxy-terminal domain.
• Revealed potential activation mechanisms for the Smc3 ATPase site, involving specific amino acid movements.
• Demonstrated sequential activation, where Smc1A ATP hydrolysis precedes and induces Smc3 ATPase activity, leading to head domain opening.

Conclusions:

• Cohesin ring opening is initiated by a sequential activation of ATP sites, with Smc1A hydrolysis preceding Smc3 activation.
• The findings provide mechanistic insights into cohesinopathies and cancers linked to cohesin dysfunction.
• This study offers a comprehensive understanding of cohesin complex dynamics at the atomic level.