The structure of the core NuRD repression complex provides insights into its interaction with chromatin

Abstract

The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities. The complex regulates the higher-order structure of chromatin, and has important roles in the regulation of gene expression, DNA damage repair and cell differentiation. HDACs 1 and 2 are recruited by the MTA1 corepressor to form the catalytic core of the complex. The histone chaperone protein RBBP4, has previously been shown to bind to the carboxy-terminal tail of MTA1. We show that MTA1 recruits a second copy of RBBP4. The crystal structure reveals an extensive interface between MTA1 and RBBP4. An EM structure, supported by SAXS and crosslinking, reveals the architecture of the dimeric HDAC1:MTA1:RBBP4 assembly which forms the core of the NuRD complex. We find evidence that in this complex RBBP4 mediates interaction with histone H3 tails, but not histone H4, suggesting a mechanism for recruitment of the NuRD complex to chromatin.DOI: http://dx.doi.org/10.7554/eLife.13941.001

Refinement of the subunit interaction network within the nucleosome remodelling and deacetylase (NuRD) complex

“…Therefore, from this set of experiments it cannot be concluded that two RBBPs directly interact. In fact, we and others have demonstrated that MTA1 can simultaneously bind two molecules of RBBP4/7 [18, 19], indicating that the apparent RBBP-RBBP interaction is likely to be indirect – mediated by MTA1/2/3. We have observed a similar phenomenon when probing for other interactions between pairs of subunits, including CHD4 and RBBP7 (Figure 3e).…”

“…Encouragingly, our data here agree closely with existing (orthogonal) structural data. That is, interactions between RBBP4 and the C-terminal half of MTA1 have been observed in several studies (Table 1 and [17–19]), MBD3 and GATAD2B are known to interact through a short coiled-coil (analogous to the MBD2-GATAD2A interaction [16]) and the ELM-SANT domain region of MTA1/2 homodimerizes in the HDAC-MTA1 structure [15]. …”

“…We also considered information from XL-MS (Table 2 and Figure 2b) [19, 39, 40]. In two studies using XL-MS on intact NuRD complex [39, 40], five interactions were identified by multiple independent crosslinks, namely MTA1/2/3-RBBP4/7 (>10 crosslinks), GATAD2A/B-MBD3 (5), MTA2–MBD3 (3), GATAD2A/B-CHD3/4 (6) and MTA1/2-CHD3/4 (4).…”

“…Further, five of the six crosslinks between CHD4 and GATAD2A/B directly reflect our observed interaction between CHD4C2 and GATAD2Bb/c. In addition, XL-MS data for a recombinant HDAC1-MTA1-RBBP4 complex show multiple connections between HDAC1 and both MTA1 and RBBP4 [19]. Crosslinks observed within a multi-protein complex do not unambiguously imply two proteins directly interact.…”

“…The complex has six core subunits, each with several paralogues: the DNA translocase CHD4 (or -3 or -5), HDAC1 (or -2), MTA1 (or -2 or -3), GATAD2A (or -B), RBBP4 (or -7) and MBD2 (or -3) (Figure 1). Structural data on subcomplexes of NuRD is becoming available [15–19], but no structure of the intact complex exists. Since 1998, a considerable body of subunit interaction data has been built up that relies on the methods described above.…”