The neural repressor NRSF/REST binds the PAH1 domain of the Sin3 corepressor by using its distinct short hydrophobic helix.
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.
Nomura
Mitsuru
M
Graduate School of Supramolecular Biology Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
Uda-Tochio
Hiroko
H
Murai
Kiyohito
K
Mori
Nozomu
N
Nishimura
Yoshifumi
Y
D000818:Animals; D001665:Binding Sites; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000138:chemical synthesis; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism; D000099229:RE1-Silencing Transcription Factor
D010446:Peptide Fragments; D012097:Repressor Proteins; D014157:Transcription Factors; D000099229:RE1-Silencing Transcription Factor; C115812:Sin3b protein, mouse