Solution structure of the interacting domains of the Mad-Sin3 complex: Implications for recruitment of a chromatin-modifying complex

Gene-specific targeting of the Sin3 corepressor complex by DNA-bound repres sors is an important mechanism of gene silencing in eukaryotes. The Sin3 co repressor specifically associates with a diverse group of transcriptional r epressors, including members of the Mad family, that play crucial roles in development. The NMR structure of the complex formed by the PAH2 domain of mammalian Sin3A with the transrepression domain (SID) of human Mad1 reveals that both domains undergo mutual folding transitions upon complex formatio n generating an unusual left-handed four-helix bundle structure and an amph ipathic alpha helix, respectively. The SID helix is wedged within a deep hy drophobic pocket defined by two PAH2 helices. Structure-function analyses o f the Mad-Sin3 complex provide a basis for understanding the underlying mec hanism(s) that lead to gene silencing.