PDBsum entry: 1xc5

Transcription corepressor

PDB id: 1xc5

Contents

Protein chain

68 a.a. *

* Residue conservation analysis

PDB id:

1xc5

Name:

Transcription corepressor

Title:

Solution structure of the smrt deacetylase activation domain

Structure:

Nuclear receptor corepressor 2. Chain: a. Fragment: deacetylase activation domain (residues 410-480). Synonym: smrt, n-cor2, silencing mediator of retinoic acid and thyroid hormone receptor, smrte, thyroid-, retinoic- acid-receptor-associated corepressor, t3 receptor- associating factor, trac, ctg repeat protein 26, smap270. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

NMR struc:

28 models

Authors:

A.Codina,J.D.Love,Y.Li,M.A.Lazar,D.Neuhaus,J.W.R.Schwabe

Key ref:

A.Codina et al. (2005). Structural insights into the interaction and activation of histone deacetylase 3 by nuclear receptor corepressors. Proc Natl Acad Sci U S A, 102, 6009-6014. PubMed id: 15837933 DOI: 10.1073/pnas.0500299102

Date:

01-Sep-04 Release date: 03-May-05

Protein chain

Q9Y618  (NCOR2_HUMAN) -  Nuclear receptor corepressor 2

Seq: 2525 a.a.

Struc: 68 a.a.

 Gene Ontology (GO) functional annotation 

• Biological process: regulation of transcription (1 term)
• Biochemical function: DNA binding (1 term)

DOI no: 10.1073/pnas.0500299102

Proc Natl Acad Sci U S A 102:6009-6014 (2005)

PubMed id: 15837933

Structural insights into the interaction and activation of histone deacetylase 3 by nuclear receptor corepressors.

A.Codina, J.D.Love, Y.Li, M.A.Lazar, D.Neuhaus, J.W.Schwabe.

ABSTRACT

SMRT (silencing mediator of retinoid acid and thyroid hormone receptor) and NCoR (nuclear receptor corepressor) are transcriptional corepressors that play an essential role in the regulation of development and metabolism. This role is achieved, in part, through the recruitment of a key histone deacetylase (HDAC3), which is itself indispensable for cell viability. The assembly of HDAC3 with the deacetylase activation domain (DAD) of SMRT and NCoR is required for activation of the otherwise inert deacetylase. The DAD comprises an N-terminal DAD-specific motif and a C-terminal SANT (SWI3/ADA2/NCoR/TFIIIB)-like domain. We report here the solution structure of the DAD from SMRT, which reveals a four-helical structure. The DAD differs from the SANT (and MYB) domains in that (i) it has an additional N-terminal helix and (ii) there is a notable hydrophobic groove on the surface of the domain. Structure-guided mutagenesis, combined with interaction assays, showed that residues in the vicinity of the hydrophobic groove are required for interaction with (and hence activation of) HDAC3. Importantly, one surface-exposed lysine is required for activation of HDAC3, but not for interaction. This lysine may play a uniquely important role in the mechanism of activating HDAC3.

Selected figure(s)

Figure 3.
Fig. 3. Comparison of the architecture (Top), electrostatic (Middle), and hydrophobic (Bottom) potential surfaces of the MYB, DAD, and SANT domains. Note the basic character of the DNA-binding surface of the MYB domain and the rather acidic nature of the corresponding surface of the SANT domain. The DAD is also rather basic. Importantly, the wider angle of helix H3 in the DAD results in a groove between the amino terminus of helix H3 and the loop between helices H1 and H2. This groove does not itself have any polar side chains, but acquires a basic charge caused by surrounding lysine residues. The hydrophobic potential of the surface [calculated by using GRID (35)] shows that whereas both the MYB and SANT domains have mostly polar surfaces, the groove in the DAD has a strikingly high hydrophobic potential, suggesting that it might mediate interactions with a nonpolar partner (36).

Figure 4.
Fig. 4. The interaction between SMRT DAD and HDAC3. (A) Effect of DAD mutations on the activation of HDAC3. The gray bars indicate the percentage of HDAC3 activity in a cotransfection assay. The numbers on the bars indicate the percentage of solvent exposure of that residue based on the lowest energy NMR structure. (B) Coimmunoprecipitation assay to monitor interaction between HDAC3 and the DAD mutants. Note that the interaction with HDAC3 mirrors the activation profile with the exception of the K449A mutation, which abolishes activation yet retains the ability to interact with HDAC3, showing that the two aspects are clearly separable. (C) Location of residues that perturb HDAC3 activity >50% (red) or <50% (green) in the structure of the DAD. Note that the residues that reduce HDAC3 activity cluster together on the surface of the DAD in the vicinity of a nonpolar groove.

Figures were selected by the author.