期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：28
页码：E3669-E3678
DOI：10.1073/pnas.1504021112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceGene transcription in eukaryotes is regulated by enzymes that posttranslationally add or remove acetyl groups from histones and render the underlying DNA more or less accessible to the transcription machinery. How histone deacetylases (HDACs), the enzymes responsible for deacetylation that are commonly found in multiprotein complexes, are assembled and targeted to their sites of action to affect transcription repression is largely unknown. We show biochemically and structurally how two key subunits of a conserved HDAC complex recruit multiple copies of HDACs into the complex in a manner that allows the enzymes to explore a large conformational space when the complex is targeted to specific genomic loci. This complex seems to be tailored for efficient deacetylation of nucleosomes that are situated far apart. Acetylation is correlated with chromatin decondensation and transcriptional activation, but its regulation by histone deacetylase (HDAC)-bearing corepressor complexes is poorly understood. Here, we describe the mechanism of assembly of the mammalian Sin3L/Rpd3L complex facilitated by Sds3, a conserved subunit deemed critical for proper assembly. Sds3 engages a globular, helical region of the HDAC interaction domain (HID) of the scaffolding protein Sin3A through a bipartite motif comprising a helix and an adjacent extended segment. Sds3 dimerizes through not only one of the predicted coiled-coil motifs but also, the segment preceding it, forming an [~]150-[IMG]f1.gif" ALT="A" BORDER="0">-long antiparallel dimer. Contrary to previous findings in yeast, Sin3A rather than Sds3 functions in recruiting HDAC1 into the complex by engaging the latter through a highly conserved segment adjacent to the helical HID subdomain. In the resulting model for the ternary complex, the two copies of the HDACs are situated distally and dynamically because of a natively unstructured linker connecting the dimerization domain and the Sin3A interaction domain of Sds3; these features contrast with the static organization described previously for the NuRD (nucleosome remodeling and deacetylase) complex. The Sds3 linker features several conserved basic residues that could potentially maintain the complex on chromatin by nonspecific interactions with DNA after initial recruitment by sequence-specific DNA-binding repressors.
