Structural basis of the specific interaction of SMRT corepressor with histone deacetylase 4.

Suk-Youl Park,Hyo-Jeong Hwang,Jaeyoung Song,Tae-Ho Jang,Gwang Sik Kim,Hee-Sae Park,Jeong-Sun Kim,Young Chul Lee,Taek-Hyun Nam

doi:10.1093/nar/gky926

Abstract

Modification of chromatin and related transcription factors by histone deacetylases (HDACs) is one of the major strategies for controlling gene expression in eukaryotes. The HDAC domains of class IIa HDACs repress the respective target genes by interacting with the C-terminal region of the silencing mediator for retinoid and thyroid receptor (SMRT) repression domain 3 (SRD3c). However, latent catalytic activity suggests that their roles as deacetylases in gene regulation are unclear. Here, we found that two conserved GSI-containing motifs of SRD3c are critical for HDAC4 binding. Two SMRT peptides including these motifs commonly form a β-hairpin structure in the cleft and block the catalytic entry site of HDAC4. They interact mainly with class IIa HDAC-specific residues of HDAC4 in a closed conformation. Structure-guided mutagenesis confirmed critical interactions between the SMRT peptides and HDAC4 and –5 as well as the contribution of the Arg1369 residue in the first motif for optimal binding to the two HDACs. These results indicate that SMRT binding does not activate the cryptic deacetylase activity of HDAC4 and explain how class IIa HDACs and the SMRT-HDAC3 complex are coordinated during gene regulation.

Highlights

As the principal enzymes involved in the epigenetic control of eukaryotic transcription, histone acetyltransferases (HATs) and histone deacetylases (HDACs) play central roles in regulating chromatin remodeling via histone tail modifications [1]
The catalytic domain of class IIa HDACs can act as a scaffold module that is responsible for recruiting the silencing mediator for retinoid and thyroid receptor (SMRT)/nuclear receptorcorepressor (NCoR)-HDAC3 complex, regardless of its deacetylase activity [17]
We examined the contribution of putative GSI motifs of SRD3T (R1128–K1592) to its binding to HDACs, indicating that GSI motifs within the SMRT RD3c (SRD3c) region function as major binding elements (Supplementary Figure S1)

Summary

INTRODUCTION

As the principal enzymes involved in the epigenetic control of eukaryotic transcription, histone acetyltransferases (HATs) and histone deacetylases (HDACs) play central roles in regulating chromatin remodeling via histone tail modifications [1]. Nucleic Acids Research, 2018, Vol 46, No 22 11777 ubiquitously expressed homologous proteins and contain highly conserved autonomous repression domains (RDs), namely, RD1–RD3, in their N-terminal regions [14,15] Both SMRT and NCoR have been shown to form a large steady-state complex with HDAC3, the class I HDAC, through the association of the deacetylaseactivating domain (DAD) of SMRT with HDAC3 [16,17]. The C-terminal region of RD3 (RD3c) of SMRT/NCoR interacts with class IIa HDACs but not with class I enzymes; SMRT/NCoR functions as a bridge factor between HDAC3 and HDAC4/-5 [18,19,20] In this regard, the catalytic domain of class IIa HDACs can act as a scaffold module that is responsible for recruiting the SMRT/NCoR-HDAC3 complex, regardless of its deacetylase activity [17]. The detailed interactions between the SMRT peptides and HDAC4c and HDAC5c have been confirmed

MATERIALS AND METHODS

RESULTS

DISCUSSION