Two-step ATP-driven opening of cohesin head.
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2017
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Scientific Reports
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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.