The neural repressor NRSF/REST binds the PAH1 domain of the Sin3 corepressor by using its distinct short hydrophobic helix

J Mol Biol. 2005 Dec 9;354(4):903-15. doi: 10.1016/j.jmb.2005.10.008. Epub 2005 Oct 26.


In non-neuronal cells and neuronal progenitors, many neuron-specific genes are repressed by a neural restrictive silencer factor (NRSF)/repressor element 1 silencing transcription factor (REST), which is an essential transcriptional repressor recruiting the Sin3-HDAC complex. Sin3 contains four paired amphipathic helix (PAH) domains, PAH1, PAH2, PAH3 and PAH4. A specific target repressor for Sin3 is likely to bind to one of them independently. So far, only the tertiary structures of PAH2 domain complexes, when bound to the Sin3-interacting domains of Mad1 and HBP1, have been determined. Here, we reveal that the N-terminal repressor domain of NRSF/REST binds to the PAH1 domain of mSin3B, and determine the structure of the PAH1 domain associated with the NRSF/REST minimal repressor domain. Compared to the PAH2 structure, PAH1 holds a rather globular four-helix bundle structure with a semi-ordered C-terminal tail. In contrast to the amphipathic alpha-helix of Mad1 or HBP1 bound to PAH2, the short hydrophobic alpha-helix of NRSF/REST is captured in the cleft of PAH1. A nuclear hormone receptor corepressor, N-CoR has been found to bind to the PAH1 domain with a lower affinity than NRSF/REST by using its C-terminal region, which contains fewer hydrophobic amino acid residues than the NRSF/REST helix. For strong binding to a repressor, PAH1 seems to require a short alpha-helix consisting of mostly hydrophobic amino acid residues within the repressor. Each of the four PAH domains of Sin3 seems to interact with a characteristic helix of a specific repressor; PAH1 needs a mostly hydrophobic helix and PAH2 needs an amphipathic helix in each target repressor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Hydrophobic and Hydrophilic Interactions
  • Mice
  • Models, Molecular
  • Nuclear Magnetic Resonance, Biomolecular
  • Peptide Fragments / chemical synthesis
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Secondary
  • Repressor Proteins / chemistry*
  • Repressor Proteins / metabolism
  • Sequence Alignment
  • Transcription Factors / chemistry*
  • Transcription Factors / metabolism


  • Peptide Fragments
  • RE1-silencing transcription factor
  • Repressor Proteins
  • Sin3b protein, mouse
  • Transcription Factors

Associated data

  • PDB/2CZY