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.
Highlights
Maintenance of the integrity of genomic information is a supreme requirement for all living organisms
In order to evaluate whether the binding of Rad21-Cter directly induces a rearrangement at active site 1 (AS1) that favours ATP hydrolysis, we performed simulations using molecular dynamics and, for the study of the chemical events, our recently developed method for quantum mechanics/molecular mechanics - molecular dynamics (QM/MM MD): Fireball/Amber[44, 45]
We have analysed the dynamic properties of the human cohesin head domains (Smc1A-head, Smc3-head and Rad21-Cter) at the atomic level using a variety of simulation techniques
Summary
Maintenance of the integrity of genomic information is a supreme requirement for all living organisms. The DNA molecule containing such information is structurally organized in chromosomes, arranged with a number of different protein macromolecular complexes. They are devoted to a variety of functions, from the scaffolding of the chromosomal building to the regulation of the gene expression. As indicated in a recent review[4], several questions related to the structure and function of cohesin ring remain open These deal with: the precise series of events that lead to loading, entrapment, release and stable cohesion; the exact role of the nucleotide binding domains; and how ATP binding and hydrolysis affect the loading and release processes. In addition to the biochemical studies and the highly valuable information offered by the crystallized structures of the Smc head domains[5, 7], it is essential to investigate the dynamic properties at the atomic scale in order to study key aspects of cohesin behaviour as well as to analyse and predict the effect of mutations
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