Abstract
The structure of the chromatin-remodeling BAF complex provides molecular-scale mechanistic insight.
Major Finding: The structure of the chromatin-remodeling BAF complex provides molecular-scale mechanistic insight.
Approach: Cryo-electron microscopy was used for refinement to 3.7-Å resolution, enabling structural modeling.
Impact: This information has the potential to provide insight into the consequences of cancer-associated BAF-complex mutations.
Mutations affecting protein subunits of the BAF and PBAF (also known as mSWI/SNF) complexes are present in up to 20% of cancers. Extensive research has been dedicated to the molecular characterization of these chromatin-remodeling complexes, but a lack of high-resolution structural information has hindered understanding of the spatial relationships among individual subunits and with the nucleosome. He, Wu, Tian, and colleagues used cryo-electron microscopy to determine the structure of a reconstituted human BAF complex bound to a nucleosome core particle (NCP) in the absence of ATP and ADP at a resolution of 3.7 Å, revealing previously elusive molecular details and providing mechanistic insights. The BAF complex was shown to bind NCPs differently than many other chromatin remodelers—instead of interacting with nucleosomal DNA or histone tails, the BAF complex envelops the entire NCP using the BAF complex's Base module (comprising approximately 80% of the total BAF complex by mass) and its ATPase module. The ATPase motor and nucleosomal DNA were in proximity to one another, and comparison of the BAF–NCP structure with a lower-resolution structure of the ADP-bound BAF–NCP complex suggested that ATP hydrolysis could result in interactions between the ATPase domain and nucleosomal DNA, effectively pushing DNA along the NCP. Four conserved arginine residues of the C-terminal alpha helix of SMARCB1, a protein essential for the structural integrity of the BAF complex, formed contacts with an acidic patch on the nucleosome; notably, these four residues are frequently mutated in human cancers. The structure further revealed that ARID1A, the largest BAF-complex subunit and one that is commonly mutated in human cancers, serves as a stable core of the Base module, and the Base module's two SMARCC subunits act as structural scaffolds. In summary, this study elucidated the long-awaited high-resolution structure of the NCP-bound BAF complex, which will provide a basis for further molecular characterization of this cancer-linked chromatin remodeler.
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