Scientists have created an unprecedented 3-dimensional structural model of a key molecular “machine” known as the BAF complex, which modifies DNA architecture and is frequently mutated in cancer and some other diseases. The researchers, led by Cigall Kadoch, PhD, of Dana-Farber Cancer Institute, have reported the first 3-D structural “picture” of BAF complexes purified directly from human cells in their native states — rather than artificially synthesized in the laboratory -providing an opportunity to spatially map thousands of cancer-associated mutations to specific locations within the complex.
“A 3-D structural model, or ‘picture,’ of how this complex actually looks inside the nucleus of our cells has remained elusive — until now,” says Kadoch. The newly obtained model represents “the most complete picture of the human BAF complex achieved to date,” said the investigators, reporting in the journal Cell.
These new findings “provide a critical foundation for understanding human disease-associated mutations in components of the BAF complex, which are present in over 20% of human cancers and in several intellectual disability and neurodevelopomental disorders,” the authors said. These insights could help scientists understand how mutations in proteins making up the complex lead to disruption of the normal regulation of DNA and hence the expression of genes in cells, potentially causing cancerous growth of cells to form tumors. Mutations in the BAF complex, for example, are the sole cause of rare childhood cancers such as synovial sarcoma and malignant rhabdoid, and contribute to common cancers such as ovarian and lung cancers.
The BAF complex is “molecular machine,” a group of proteins that remodel the way DNA is packaged in cells. It is made up of a dozen protein subunits specified by 29 different genes. Previous attempts to obtain a structural 3-D model of the BAF complex were based on protein molecules recombinantly