A nucleotide-driven switch regulates flanking DNA length sensing by a dimeric chromatin remodeler

Area of Science:

• Chromatin biology
• Molecular mechanisms of epigenetics
• Nucleosome remodeling

Background:

• The ATP-dependent chromatin assembly factor (ACF) is crucial for organizing nucleosomes and establishing silent chromatin.
• The ATPase subunit SNF2h, existing as a dimer, interacts with nucleosomes, but the mechanism of protomer interaction and function remains unclear.
• The HAND-SANT-SLIDE (HSS) domain of SNF2h senses flanking DNA length, but its role in enhancing nucleosome remodeling is not fully understood.

Purpose of the Study:

• To investigate how SNF2h protomers interact and function within the ACF complex.
• To elucidate the role of the HSS domain in SNF2h-mediated chromatin remodeling.
• To understand the mechanism by which SNF2h senses DNA length and remodels nucleosomes.

Main Methods:

• Utilized covalently linked SNF2h dimers to study the effects of dimerization on remodeling activity.
• Investigated nucleotide-dependent conformational changes in SNF2h using biochemical assays.
• Characterized the interaction of the HSS domain with flanking DNA and the nucleosome core.

Main Results:

• Dimerization of SNF2h significantly accelerates nucleosome remodeling.
• The HSS domain plays a critical role in mediating communication between SNF2h protomers.
• Identified a nucleotide-dependent conformational switch in SNF2h, with distinct states for DNA binding and nucleosome engagement.
• Demonstrated that the HSS domain binds flanking DNA in one conformation and the nucleosome core in another.

Conclusions:

• SNF2h functions through two distinct conformational states, separating DNA length sensing and nucleosome translocation activities.
• This separation of function allows for independent regulation of remodeling outcomes.
• The findings propose a novel model for SNF2h-mediated chromatin remodeling, highlighting the importance of dimerization and conformational flexibility.