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Sci Rep. 2017 Jun 12;7(1):3266. doi: 10.1038/s41598-017-03118-9.

Two-step ATP-driven opening of cohesin head.

Author information

1
Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), 28049, Madrid, Spain.
2
Departamento de Física Teórica de la Materia Condensada and Condensed Matter Physics Center (IFIMAC), Universidad Autónoma de Madrid, 28049, Madrid, Spain.
3
Unidad de Genética Clínica y Genómica Funcional, Departamento de Farmacología-Fisiología y Departamento de Pediatría, Hospital Clínico Universitario "Lozano Blesa", Facultad de Medicina, Universidad de Zaragoza, ISS-Aragon and CIBERER-GCV02, 50009, Zaragoza, Spain.
4
Departamento de Biotecnología, Universidad Francisco de Vitoria, Pozuelo de Alarcón, 28223, Madrid, Spain.
5
Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), 28049, Madrid, Spain. pagomez@cbm.csic.es.

Abstract

The cohesin ring is a protein complex composed of four core subunits: Smc1A, Smc3, Rad21 and Stag1/2. It is involved in chromosome segregation, DNA repair, chromatin organization and transcription regulation. Opening of the ring occurs at the "head" structure, formed of the ATPase domains of Smc1A and Smc3 and Rad21. We investigate the mechanisms of the cohesin ring opening using techniques of free molecular dynamics (MD), steered MD and quantum mechanics/molecular mechanics MD (QM/MM MD). The study allows the thorough analysis of the opening events at the atomic scale: i) ATP hydrolysis at the Smc1A site, evaluating the role of the carboxy-terminal domain of Rad21 in the process; ii) the activation of the Smc3 site potentially mediated by the movement of specific amino acids; and iii) opening of the head domains after the two ATP hydrolysis events. Our study suggests that the cohesin ring opening is triggered by a sequential activation of the ATP sites in which ATP hydrolysis at the Smc1A site induces ATPase activity at the Smc3 site. Our analysis also provides an explanation for the effect of pathogenic variants related to cohesinopathies and cancer.

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