Specific conformational dynamics of the ATPase head domains and DNA exit gate mediate the Cohesin ATPase cycle

Abstract

SummaryThe Cohesin complex is key to eukaryotic genomes organization. ATP binding and hydrolysis are essential to Cohesin functions, but the molecular mechanisms underlying Cohesin ATPase activity remain poorly understood. We characterized distinct steps of the human Cohesin ATPase cycle. Non-engaged SMC1A and SMC3 ATPase domains adopt specific inactive conformations caused by a SMC1A relaxed state and a SMC3/RAD21 DNA exit gate resting state. ATP-dependent ATPase domains engagement leads to a semi-productive ATPase module with a flexible DNA exit gate, and formation of the fully productive ATPase module requires a SMC1A/SMC3 interface reorganization through NIPBL and DNA binding. Functional analyses in zebrafish demonstrate the importance of the full DNA exit gate and its dynamic. The distinct states and concerted movements of Cohesin ATPase domains and DNA exit gate thus mediate the Cohesin ATPase cycle and can be targeted by Cohesin regulators.