We use advanced tools in structural biology, such as crystallography and cryo-electron microscopy, in combination with biochemistry, genetics and other methods, to analyze chromatin-related molecular machines.
Overall structure of Snf2-nucleosome complex in different nucleotide states and DNA wave model
Chromatin remodelers use energy from ATP hydrolysis to reposite nucleosomes around genomic DNA sites and remodel chromatin. They play important roles in shaping chromatin structures and controlling gene expression, cell fate determination, and human diseases. How chromatin remodelers use the energy of ATP hydrolysis to promote nucleosome sliding is a puzzling question.
Chromatin remodeling is a multi-step dynamic process coupled with ATP hydrolysis. The main challenge to the mechanisms of chromatin remodeling concerns how the remodeler enzymes overcome the extensive histone–DNA interactions to slide the nucleosome. To tease these mechanisms apart, it was necessary to establish how chromatin remodelers interact with the nucleosome. In 2016, we determined the crystal structures of Snf2 and ISWI motor domains. In 2017, we determined the cryoEM structure of the motor domains of Snf2 bound to the nucleosome in the nucleotide-free, apo state, which provided the first glimpse into the motor-nucleosome interaction. In 2019, we then determined the structures of Snf2 and ISWI bound to the nucleosome in the presence of ADP and ADP-BeFx. Together, our findings suggest a fundamental mechanism for the DNA translocation that underlies chromatin remodelling.
A two-step "DNA wave" model for chromatin remodeling: In the first step, ATP hydrolyzes, Snf2 opens, pulls DNA in from the inlet end, and stores 1bp DNA deformation at SHL2 (" DNA wave "); In the second step, ATP binds and Snf2 is turned off, allowing the DNA to deform and move toward the exit, just like water waves move across a lake, eventually allowing DNA to move relative to histones. This model suggests that Snf2 hydrolyzes one ATP and moves 1bp of DNA. It also explains the directional mechanism by which DNA moves.