A structural model of the human mSWI/SNF (BAF) complex bound to the nucleosome informs disease mechanisms

Mammalian SWI/SNF complexes are multi-component ATP-dependent chromatin-remodeling complexes that regulate genomic architecture. Here we present the first structural model of the human canonical BAF chromatin-remodeling complex bound to a nucleosome generated using cryo-EM, cross-linking mass spectrometry, and homology modeling. Endogenously-purified BAF tethers to the nucleosome H2A/H2B acidic patch regions bilaterally through the SMARCB1 C-terminal helix and a SMARCA4 C-terminal post-SnAc region, each of which are mutated in disease and disrupt nucleosome remodeling. We describe the structural organization of the BAF core module, a connecting ARP module and the ATPase module, scaffolded by the SMARCA4/2 ATPase subunits. Importantly, we assign and model disease-associated mutations throughout the entire BAF complex, identifying mutations that break identified subunit–nucleosome contacts and subunit–subunit interfaces of BAF in the nucleosome-bound conformation. Taken together, this comprehensive structural model of the human BAF complex provides the first insights into the functional impact of mutations that cause cancer and other diseases.