The Nucleosome Remodeling and Deacetylase (NuRD) complex is essential for development in complex animals but has been refractory to biochemical analysis. We present the first integrated analysis of the architecture of the native mammalian NuRD complex, combining quantitative mass spectrometry, covalent cross-linking, protein biochemistry and electron microscopy. NuRD is built around a 2:2:4 pseudo-symmetric deacetylase module comprising MTA, HDAC and RBBP subunits. This module interacts asymmetrically with a remodeling module comprising one copy each of MBD, GATAD2 and CHD subunits. The previously enigmatic GATAD2 controls the asymmetry of the complex and directly recruits the ATP-dependent CHD remodeler. Unexpectedly, the MTA-MBD interaction acts as a point of functional switching. The transcriptional regulator PWWP2A modulates NuRD assembly by competing directly with MBD for binding to the MTA-HDAC-RBBP subcomplex, forming a 'moonlighting' PWWP2A-MTA-HDAC-RBBP complex that likely directs deacetylase activity to PWWP2A target sites. Taken together, our data describe the overall architecture of the intact NuRD complex and reveal aspects of its structural dynamics and functional plasticity. INO80(1, 2) and SWR1 complexes (3), as well as to the Snf2 (4) and Chromodomain-Helicase-DNA-binding 1 (CHD1) remodelers (5), our understanding of how such enzymes bring about remodeling is still underdeveloped. This is particularly true for the nucleosome remodeling and deacetylase (NuRD) complex.The NuRD complex is widely distributed among Metazoans and is expressed in most, if not all, tissues. It is essential for normal development (6, 7) and is a key regulator in the reprogramming of differentiated cells into pluripotent stem cells (8-10). Age-related reductions in NuRD subunit levels are strongly associated with memory loss, metastatic potential in human cancers (11), and the accumulation of chromatin defects (12, 13).The mammalian NuRD complex comprises at least six subunits (Figure S1a), and for each subunit there are at least two paralogues, giving the potential for significant compositional heterogeneity. CHD4 (and its paralogues CHD3 and -5) is the ATP-dependent DNA translocase in the complex and harbours several regulatory and targeting domains. For example, the PHD domains of CHD4 can recognize histone H3 N-terminal tails bearing methyllysine marks (14-16), and the HMG domain has been shown to bind to poly-ADP(ribose) (17). What distinguishes NuRD from many other remodelers is that it harbours a second catalytic activity, imparted by the histone deacetylases HDAC1 and -2. MBD2 and -3 can bind hydroxymethylated and/or methylated , and RBBP4 and -7 can each bind histone tails (21) and other transcriptional regulators (22,23). The metastasis-associated proteins MTA1, -2 and -3 contain several domains that are associated with nucleosome recognition, whereas GATAD2A and GATAD2B bind to both 25) and CHD proteins (25, 26) but otherwise do not have known functions. Some structural information is available for portions of t...

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