Structural insights into the assembly of the histone deacetylase-associated Sin3L/Rpd3L corepressor complex

Structural insights into the assembly of the histone deacetylase-associated Sin3L/Rpd3L corepressor complex

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 conserv...

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Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 28; pp. E3669 - E3678
Main Authors: Clark, Michael D, Ryan Marcum, Richard Graveline, Clarence W. Chan, Tao Xie, Zhonglei Chen, Yujia Ding, Yongbo Zhang, Alfonso Mondragón, Gregory David, Ishwar Radhakrishnan
Format: Journal Article
Language:English
Published: United States National Academy of Sciences 14-07-2015
National Acad Sciences
Series:PNAS Plus
Subjects:
Amino Acid Sequence
Animals
BASIC BIOLOGICAL SCIENCES
Biological Sciences
Chromatin
corepressor complex
Correlation analysis
Deoxyribonucleic acid
Dimerization
DNA
eukaryotic cells
histone deacetylase
Histone Deacetylases - metabolism
histones
loci
Magnetic Resonance Spectroscopy
Molecular Sequence Data
multiprotein complexes
nucleosomes
PNAS Plus
Protein Conformation
Proteins
protein–protein interaction
protein–protein interaction
Repressor Proteins - chemistry
Repressor Proteins - metabolism
Sequence Homology, Amino Acid
structural biology
transcription (genetics)
transcription repression
protein–protein interaction
structural biology
transcription repression
corepressor complex
histone deacetylase
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Summary: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-óÅ-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. Gene 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.
Bibliography:http://dx.doi.org/10.1073/pnas.1504021112
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content type line 23
Northwestern Summer Undergraduate Research Grants
Achievement Rewards for College Scientists Foundation Fellowship
T32GM008382; R01GM64715; 14GRNT20170003
National Institutes of Health (NIH)
American Heart Association (AHA)
Molecular Biophysics Training Grant
Edited by Kevin Struhl, Harvard Medical School, Boston, MA, and approved May 28, 2015 (received for review February 26, 2015)
Author contributions: M.D.C., R.M., R.G., G.D., and I.R. designed research; M.D.C., R.M., R.G., C.W.C., T.X., Z.C., Y.D., Y.Z., and G.D. performed research; M.D.C., R.M., R.G., C.W.C., T.X., Z.C., Y.D., A.M., G.D., and I.R. analyzed data; and M.D.C., R.M., R.G., C.W.C., G.D., and I.R. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1504021112