Coupled unfolding and dimerization by the PAH2 domain of the mammalian Sin3A corepressor.
Coregulator recruitment by sequence-specific DNA binding transcription factors constitutes an important step in many eukaryotic transcription regulatory pathways. The Sin3 corepressor is an evolutionarily conserved protein and a key component of a large histone deacetylase-associated corepressor complex. The Sin3 corepressor contains four imperfect repeats of a domain called PAH (paired amphipathic helix) that serve as docking sites for a variety of sequence-specific DNA binding factors and coregulators. At least two closely related Sin3 proteins designated Sin3A and Sin3B have been described in higher organisms and although functional differences between these paralogs are only beginning to be appreciated, differences at the structural level are poorly understood. Here we analyze the conformational properties of the apo form of the mammalian Sin3A (mSin3A) PAH2 domain. At low micromolar concentrations, the domain is predominantly monomeric and folded in a conformation similar to those found in complexes with the Mad1 and HBP1 repressors. Unexpectedly, at higher concentrations, the domain dimerizes with concomitant population of a partially unfolded conformer. These findings are in contrast to those reported for the mSin3B PAH2 domain and may have implications for the manner in which these paralogous domains interact with their targets.
Zhang
Yongbo
Y
Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, Evanston, Illinois 60208-3500, USA.
Zhang
Zhipeng
Z
Demeler
Borries
B
Radhakrishnan
Ishwar
I
D000595:Amino Acid Sequence; D000818:Animals; D019143:Evolution, Molecular; D006657:Histones / Q000737:chemistry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D011485:Protein Binding; D011489:Protein Denaturation; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D056264:Sin3 Histone Deacetylase and Corepressor Complex
D006657:Histones; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D056264:Sin3 Histone Deacetylase and Corepressor Complex