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

doi:10.1016/j.celrep.2020.108450

The Nucleosome Remodeling and Deacetylase Complex Has an Asymmetric, Dynamic, and Modular Architecture

Cell Rep. 2020 Dec 1;33(9):108450. doi: 10.1016/j.celrep.2020.108450.

Authors

Jason K K Low¹, Ana P G Silva², Mehdi Sharifi Tabar², Mario Torrado², Sarah R Webb², Benjamin L Parker², Maryam Sana², Callum Smits³, Jason W Schmidberger², Lou Brillault⁴, Matthew J Jackman⁴, David C Williams Jr⁵, Gerd A Blobel⁶, Sandra B Hake⁷, Nicholas E Shepherd², Michael J Landsberg⁸, Joel P Mackay⁹

Affiliations

¹ School of Life and Environmental Sciences, University of Sydney, NSW, Australia. Electronic address: jason.low@sydney.edu.au.
² School of Life and Environmental Sciences, University of Sydney, NSW, Australia.
³ Sydney, NSW, Australia.
⁴ School of Chemistry and Molecular Biosciences, University of Queensland, QLD, Australia.
⁵ Dept of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, NC, USA.
⁶ The Division of Hematology, Children's Hospital of Philadelphia, and the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷ Institute for Genetics, FB08 Biology, Justus-Liebig-University Giessen, Giessen, Germany.
⁸ School of Chemistry and Molecular Biosciences, University of Queensland, QLD, Australia. Electronic address: m.landsberg@uq.edu.au.
⁹ School of Life and Environmental Sciences, University of Sydney, NSW, Australia. Electronic address: joel.mackay@sydney.edu.au.

Abstract

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.

Keywords: DIA-MS; EM; NuRD; PWWP2A; cross-linking MS; electron microscopy; gene regulation; nucleosome remodeling.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Gene Expression Regulation / genetics*
Histone Deacetylases / metabolism*
Humans
Models, Molecular
Nucleosomes / metabolism*

Substances

Nucleosomes
Histone Deacetylases

Abstract

Publication types

MeSH terms

Substances

Grants and funding