The bHLH-ZIP protein Mad heterodimerizes with Max as a sequence-specific transcriptional repressor. Mad is rapidly induced upon differentiation, and the associated switch from Myc-Max to Mad-Max heterocomplexes seem to repress genes normally activated by Myc-Max. We have identified two related mammalian cDNAs that encode Mad-binding proteins. Both possess sequence homology with the yeast transcription repressor Sin3, including four conserved paired amphipathic helix (PAH) domains. mSin3A and mSin3B bind specifically to Mad and the related protein Mxi1. Mad-Max and mSin3 form ternary complexes in solution that specifically recognize the Mad-Max E box-binding site. Mad-mSin3 association requires PAH2 of mSin3A/mSin3B and the first 25 residues of Mad, which contains a putative amphipathic alpha-helical region. Point mutations in this region eliminate interaction with mSin3 proteins and block Mad transcriptional repression. We suggest that Mad-Max represses transcription by tethering mSin3 to DNA as corepressors and that a transcriptional repression mechanism is conserved from yeast to mammals.
The SCAN domain is described as a highly conserved, leucine-rich motif of approximately 60 amino acids found at the amino-terminal end of zinc finger transcription factors. Although no specific biological function has been attributed to the SCAN domain, its predicted amphipathic secondary structure led to the suggestion that this domain may mediate protein-protein associations. The SCAN or leucine-rich domain, originally identified by its homology with similar elements in several zinc finger transcription factors, consists of approximately 60 amino acids and is rich in leucine and glutamic acid residues (1). Most SCAN domain sequences are linked to Cys 2 -His 2 zinc finger motifs through their carboxyl-terminal end. Although the function of the SCAN domain has not yet been elucidated, the predicted amphipathic structure of the domain led to the suggestion that SCAN box elements have the capacity to interact with other proteins, in particular with components of the transcriptional machinery (1).The zinc finger protein ZNF202 1 is expressed in two common splice variants, here referred to as m1 and m3 (2). Whereas the m1-splice form encodes a full-length protein of 648 amino acids with a SCAN box, a KRAB repression domain, and eight Cys 2 -His 2 zinc finger motifs, the 133 amino acid product of the m3-splice form encompasses only the SCAN domain.2 These splice forms are conserved in the murine ZNF202 homolog, suggesting that the SCAN motif itself is an independent functional domain.3
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