The Nucleosome Remodeling and Deacetylase Complex Has an Asymmetric, Dynamic, and Modular Architecture
Jason K.K. Low,
Ana P.G. Silva,
Mehdi Sharifi Tabar,
Mario Torrado,
Sarah R. Webb,
Benjamin L. Parker,
Maryam Sana,
Callum Smits,
Jason W. Schmidberger,
Lou Brillault,
Matthew J. Jackman,
David C. Williams, Jr.,
Gerd A. Blobel,
Sandra B. Hake,
Nicholas E. Shepherd,
Michael J. Landsberg,
Joel P. Mackay
Affiliations
Jason K.K. Low
School of Life and Environmental Sciences, University of Sydney, NSW, Australia; Corresponding author
Ana P.G. Silva
School of Life and Environmental Sciences, University of Sydney, NSW, Australia
Mehdi Sharifi Tabar
School of Life and Environmental Sciences, University of Sydney, NSW, Australia
Mario Torrado
School of Life and Environmental Sciences, University of Sydney, NSW, Australia
Sarah R. Webb
School of Life and Environmental Sciences, University of Sydney, NSW, Australia
Benjamin L. Parker
School of Life and Environmental Sciences, University of Sydney, NSW, Australia
Maryam Sana
School of Life and Environmental Sciences, University of Sydney, NSW, Australia
Callum Smits
Sydney, NSW, Australia
Jason W. Schmidberger
School of Life and Environmental Sciences, University of Sydney, NSW, Australia
Lou Brillault
School of Chemistry and Molecular Biosciences, University of Queensland, QLD, Australia
Matthew J. Jackman
School of Chemistry and Molecular Biosciences, University of Queensland, QLD, Australia
David C. Williams, Jr.
Dept of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, NC, USA
Gerd A. Blobel
The Division of Hematology, Children’s Hospital of Philadelphia, and the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Sandra B. Hake
Institute for Genetics, FB08 Biology, Justus-Liebig-University Giessen, Giessen, Germany
Nicholas E. Shepherd
School of Life and Environmental Sciences, University of Sydney, NSW, Australia
Michael J. Landsberg
School of Chemistry and Molecular Biosciences, University of Queensland, QLD, Australia; Corresponding author
Joel P. Mackay
School of Life and Environmental Sciences, University of Sydney, NSW, Australia; Corresponding author
Summary: The nucleosome remodeling and deacetylase (NuRD) complex is essential for metazoan development but has been refractory to biochemical analysis. We present an integrated analysis of the native mammalian NuRD complex, combining quantitative mass spectrometry, cross-linking, protein biochemistry, and electron microscopy to define the architecture of the complex. NuRD is built from a 2:2:4 (MTA, HDAC, and RBBP) deacetylase module and a 1:1:1 (MBD, GATAD2, and Chromodomain-Helicase-DNA-binding [CHD]) remodeling module, and the complex displays considerable structural dynamics. The enigmatic GATAD2 controls the asymmetry of the complex and directly recruits the CHD remodeler. The MTA-MBD interaction acts as a point of functional switching, with the transcriptional regulator PWWP2A competing with MBD for binding to the MTA-HDAC-RBBP subcomplex. Overall, our data address the long-running controversy over NuRD stoichiometry, provide imaging of the mammalian NuRD complex, and establish the biochemical mechanism by which PWWP2A can regulate NuRD composition.
