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A Structural Model of the Endogenous Human BAF Complex Informs Disease Mechanisms.
Mashtalir, Nazar; Suzuki, Hiroshi; Farrell, Daniel P; Sankar, Akshay; Luo, Jie; Filipovski, Martin; D'Avino, Andrew R; St Pierre, Roodolph; Valencia, Alfredo M; Onikubo, Takashi; Roeder, Robert G; Han, Yan; He, Yuan; Ranish, Jeffrey A; DiMaio, Frank; Walz, Thomas; Kadoch, Cigall.
Afiliación
  • Mashtalir N; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Suzuki H; Laboratory of Molecular Electron Microscopy, The Rockefeller University, New York, NY, USA.
  • Farrell DP; Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Sankar A; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Luo J; Institute for Systems Biology, Seattle, WA, USA.
  • Filipovski M; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • D'Avino AR; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • St Pierre R; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Chemical Biology Program, Harvard Medical School, Boston, MA, USA.
  • Valencia AM; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Chemical Biology Program, Harvard Medical School, Boston, MA, USA.
  • Onikubo T; Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY, USA.
  • Roeder RG; Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY, USA.
  • Han Y; Department of Molecular Biosciences, Northwestern University, Evanston, IL, USA.
  • He Y; Department of Molecular Biosciences, Northwestern University, Evanston, IL, USA.
  • Ranish JA; Institute for Systems Biology, Seattle, WA, USA.
  • DiMaio F; Department of Biochemistry, University of Washington, Seattle, WA, USA. Electronic address: dimaio@u.washington.edu.
  • Walz T; Laboratory of Molecular Electron Microscopy, The Rockefeller University, New York, NY, USA. Electronic address: twalz@rockefeller.edu.
  • Kadoch C; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: cigall_kadoch@dfci.harvard.edu.
Cell ; 183(3): 802-817.e24, 2020 10 29.
Article en En | MEDLINE | ID: mdl-33053319
ABSTRACT
Mammalian SWI/SNF complexes are ATP-dependent chromatin remodeling complexes that regulate genomic architecture. Here, we present a structural model of the endogenously purified human canonical BAF complex bound to the nucleosome, generated using cryoelectron microscopy (cryo-EM), cross-linking mass spectrometry, and homology modeling. BAF complexes bilaterally engage the nucleosome H2A/H2B acidic patch regions through the SMARCB1 C-terminal α-helix and the SMARCA4/2 C-terminal SnAc/post-SnAc regions, with disease-associated mutations in either causing attenuated chromatin remodeling activities. Further, we define changes in BAF complex architecture upon nucleosome engagement and compare the structural model of endogenous BAF to those of related SWI/SNF-family complexes. Finally, we assign and experimentally interrogate cancer-associated hot-spot mutations localizing within the endogenous human BAF complex, identifying those that disrupt BAF subunit-subunit and subunit-nucleosome interfaces in the nucleosome-bound conformation. Taken together, this integrative structural approach provides important biophysical foundations for understanding the mechanisms of BAF complex function in normal and disease states.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Modelos Moleculares / Enfermedad / Complejos Multiproteicos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Cell Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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PubMed Links
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Modelos Moleculares / Enfermedad / Complejos Multiproteicos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Cell Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos